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Building a Better Bacteria: Stripped-Down E. Coli Could Help Vaccine-Makers

Posted on: Friday, 28 April 2006, 03:04 CDT

By Susanne Rust, Milwaukee Journal Sentinel

Apr. 28--In what could be a boon to development of vaccines and targeted therapies, a researcher at the University of Wisconsin-Madison, in collaboration with a team of international researchers, has created a streamlined, hardy form of the E. coli bacterium reducing its DNA to its bare essentials.

This feat could enable pharmaceutical companies to start manufacturing reliable DNA-based vaccines and gene therapies that can be created in large quantities.

Using his extensive knowledge of E. coli in combination with a set of sophisticated molecular tools, Frederick Blattner, a UW geneticist, stripped more than 15% of the bacteria's genome away, revealing a benign but laboratory-friendly organism that both research and industry are excited about.

"The potential is quite good," said Anthony Green, distinguished scientist at Puresyn Inc., a Pennsylvania pharmaceutical contract manufacturer that specializes in plasmid and gene transfer products, who wasn't involved in the study.

"Not only will it allow us to have better, more reliable fermentation" of bacteria, which is essential for large-scale, high-quality manufacturing, he said, but it also will alleviate some potential, albeit theoretical, safety issues that have shadowed the burgeoning industry.

The paper appeared in this week's online edition of the journal Science.

Blattner, who is considered one of the foremost E. coli researchers in the world, first sequenced the bacteria's genome in 1997. It wasn't long after this feat that he started comparing different strains -- placing the circular genomes of several strains side side.

It soon became apparent that many of the genes in these strains were completely different, while other parts were nearly identical. Knowing a bit about how bacteria reproduce and acquire new genes, he wondered if these starkly different bits of DNA were essential for the well-being of this bacteria.

One of the ways bacteria acquire and lose genes is through a process called horizontal transfer: They meet up with other bacteria or viruses and exchange bits of DNA. Were these differences, then, the result of bacterial "trades?"

If that were the case, they might not be necessary for the basic functioning of the E. coli.

So, he started to whittle these "excess" genes away, eventually removing more than 15% of the entire genome. He discovered that not only could he remove genes that make the bacteria harmful or genes that didn't do much of anything, but in so doing, he was able to uncover an organism that was particularly hardy and prolific.

"It's like turning a 6-cylinder engine into a 4-cylinder, without sacrificing quality, but giving it better gas mileage," Green said.

Indeed, without having to spend excess energy on features that aren't necessary for its existence, it can reproduce a lot faster.

And that's in part why drug manufacturers such as Green are so giddy.

For years, researchers have been interested in the developing field of synthetic biology -- an area of science in which scientists dreamed of molding the entire genomes of bacteria and viruses in new and unprecedented ways.

In other words, "trying to get bacteria to jump through flaming hoops," said George Weinstock, a researcher in the department of molecular and human genetics at the Baylor College of Medicine in Houston, who was not involved in the study

Human applications

The promise behind this field lies in its usefulness for DNA-targeted drug manufacturing and treatment of disease. This strategy allows researchers to create or clone tailor-made DNA sequences in the form of plasmids -- circular bacterial DNA -- which they then could insert into the human body, conceivably triggering the body to create the proteins it needs to fight or ward off disease.

Green said, "In theory, it should be more efficient to introduce the genes that make a protein," as opposed to the protein itself, which is the way most vaccines work today.

Indeed, not only would it be more efficient once introduced into the body, but it should streamline the manufacturing process, too.

Growing large quantities of DNA for therapeutic applications, which is essentially the role of E. coli in this kind of drug manufacturing, is difficult and only recently being addressed.

"Instead of going through eggs," as flu vaccine manufacturers do, and trying to guess which strain is going to appear while still producing enough for that season, vaccine-makers could have a "set of plasmids that have all the flu serotypes," and get E. coli to spew out the vaccine in large amounts in a short period of time, Green said.

The problem has been that E. coli is prone to quality-control problems. For one, it's somewhat of a slow cloner. For another, its ability to pick up genes from unwanted bacteria and viruses has made it less than reliable in some cases and theoretically harmful in others.

Blattner's work should strip E. coli of these problems, Green said, enabling it to produce high volumes of DNA with relatively little concern about introducing harmful or unwanted DNA.

And while this second concern is largely theoretical, Green said, it is one of the issues hanging over the development of these kinds of medicines. Indeed, no human DNA vaccines are on the market.

"We've combined a purest idea with a practical application," Blattner said.

The organism has been patented Wisconsin Alumni Research Foundation and licensed to Blattner's company, Scarab Genomics.

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Copyright (c) 2006, Milwaukee Journal Sentinel

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Source: The Milwaukee Journal Sentinel

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