Science Editor

With the Beijing Olympics in full swing, the Chinese news about things that aren't what they seem has focused on underage gymnasts with fake passports.

But earlier this year, the Chinese penchant for mislabeling had far deadlier consequences. Contaminated heparin, an anticoagulant that is used to prevent blood clots in both surgery and kidney dialysis, killed more than 80 and sickened many more patients who were taking the drug. (See BioWorld Today, March 3, 2008, and March 18, 2008.)

The contaminant ultimately was identified as oversulfated chondroitin sulfate.

Batches of heparin now can be tested for that specific contaminant, thanks in part to the work of Robert Linhardt of the Rensselaer Polytechnic Institute whose laboratory helped identify the contaminant this spring.

But at the American Chemical Society fall meeting in New Orleans this week, Linhardt described a new method for making heparin synthetically through E. coli fermentation, arguing that identifying the oversulfated chondroitin sulfate as a contaminant was "only a short-term solution" and that the process by which heparin currently is made is "inherently susceptible to contamination."

The starting material for pharmaceutical heparin derives from the intestinal lining of pigs.

In China, which supplies more than half of the world's heparin supply, most of those pigs are raised on small family farms. But any bucolic charm of this notion wears off fast when combined with what Linhardt termed "a very low level of regulatory control" that leaves the manufacturing of raw material in the largely unsupervised hands of "mom-and-pop-type operations," with an uncontrolled mix of species at the slaughterhouse, followed by widely varying hygiene standards for drying and scraping the intestinal lining to generate the raw material for heparin.

That raw material is, of course, processed and purified under much more stringent conditions once it reaches the hands of pharmaceutical companies. But nevertheless, Linhardt told reporters at a press conference on Sunday, the current way the raw materials are harvested means that oversulfated chondroitin sulfate is "only one contaminant" of many that could lead to further problems with the heparin supply.

Potential sources, he said, include compounds in the pigs' feed that associate with the intestinal lining, and viruses or prions the pigs could be infected with, as well as impurities that can get into the heparin during the manufacturing process.

The obvious alternative is to produce heparin synthetically; but because of the complexity of the molecule, earlier attempts to make synthetic heparin have been successful, but only in microgram quantities.

Linhardt's team was able to synthesize milligram quantities of heparin by using an approach termed chemoenzymatic synthesis in E. coli.

E. coli makes a sugar that is identical to the heparin backbone. The researchers then isolate that sugar and use recombinant enzymes to turn that backbone into heparin. Linhardt said that it would be desirable to put the entire processing pathway into E. coli, but said that due to the complexity of heparin's glycosylation, that is not possible at this time.

The new technique is a long way from making the literally tons of heparin that are used annually worldwide. So far, Linhardt and his team have synthesized 100 mg, or the equivalent of one clinical dose, making it necessary to scale up production by about nine orders of magnitude.

Linhardt said that he and his colleagues hope to be producing heparin on the kilogram scale within five years. At that point, he hopes that a biotechnology or pharmaceutical company will be interested in commercializing heparin based on the approach.

While several companies have expressed interest in his findings, heparin is a commodity that is sold at low cost, making basic research into the scale-up of alternative production methods an unappealing prospect commercially. "Their interest is in something that's a bit further along," he added.