Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.

Bacteria called Actinomyces have been known for half a century as a limitless mother lode of antibiotic drugs and anticancer agents. To wit: erythromycin, tetracycline, vancomycin, streptomycin, doxorubicin. Add to that list the enediynes, a rare and potent class of antitumor antibiotics.

But a major Catch-22 beclouds the lavish generosity of the Actinomyces bugs, including the enediynes. The former cause severe diseases in people they infect, and the latter are too toxic for human consumption.

Ecopia BioSciences Inc., of Montreal, is not taking these hang-ups lying down. The company is deploying its proprietary high-throughput genome-scanning technology to those drug-producing bacteria, to discover novel therapeutic compounds. Their methodology is described in the February 2003 issue of Nature Biotechnology, published online Jan. 21, 2003, under the title: "A genomics-guided approach for discovering and expressing cryptic metabolic pathways."

"It offers the potential of identifying antibacterial, antifungal and anticancer agents that have been overlooked using traditional discovery techniques," the article's senior author, Chris Farnet, told BioWorld Today. He is chief scientific officer of Ecopia. "Our work," Farnet added, "clearly demonstrates the utility of genome analysis in discovering new microbial natural products. Rather than sequence the Actinomyces bacterium's whole genome," he explained, "the company takes a shotgun sequencing approach to generate short DNA segments - called genome sequencing tags (GSTs). This provides an efficient way to discover natural-product gene clusters because a relatively small number of GSTs provide reasonable assurance of full genome representation."

As reported in the journal article, the efficacy of Ecopia's genome-scanning method is demonstrated by its work with enediynes. That approach had been used to isolate natural-product biosynthetic gene clusters from a variety of Actinomycetea strains - but not enediynes. "Surprisingly," Farnet recalled, "eight out of the 50 strains we analyzed had gene clusters that indicated the potential for producing enediyene products. Similarly, another three strains out of 20 were identified by scanning the genomes of a random sample of the bacterial strains that had been recently isolated from soil samples. (See BioWorld Today, Aug. 16, 2002, p. 1.)

"We then validated enediyene production in all 11 strains, and concluded it's likely that some of the previously unknown biosynthetic gene clusters produce new classes of this antitumor agent. The Actinomycetes have been pharma's favorite microbe for decades," Farnet observed, "but there has been a suspicion that maybe the well had run dry. Our paper shows that you just need to drill deeper. This is the first genomics-based, high-throughput technology for drug discovery from microorganisms. We think it will lead to a renaissance of interest," he concluded, "as a source of drug leads."

Randomized, Placebo-Controlled Trial Of IL-11 Saved Cancer Patients From Toxic Antibodies

The toxic effects of chemotherapy to treat blood cancers cause pathogenic organisms lurking in the gut to migrate to the bloodstream, frequently resulting in bacterial infection. Clinicians at Tawam Hospital in the United Arab Emirates conceived of an end-run around this predicament. Results of their double-blind, placebo-controlled clinical trial are reported in the current issue of The Lancet, dated Jan. 25, 2003.

Their paper is titled: "Recombinant human interleukin-11 and bacterial infection in patients with hematological malignant disease undergoing chemotherapy: a double-blind placebo-controlled randomized trial."

Recombinant human interleukin-11 is an immune system cytokine that increases the number of blood platelets. It is used to ameliorate severe thrombocytopenia resulting from cancer chemotherapy. "Prompt treatment of individuals with febrile neutropenia with broad-spectrum antibiotics reduces infection-related mortality," the paper pointed out, "but high cost, emergent resistance and toxicity are disadvantages." (RhIL-11 downregulates inflammatory responses, which might ameliorate sepsis.)

The article's lead author, Michael Ellis, describes their rationale: "The administration of IL-11 reduces bacteremia, predominantly of gastrointestinal origin, in patients with hematological malignant disease undergoing chemotherapy. The number of patients enrolled was small, so larger clinical trials should be done to confirm our findings. If they are substantiated, IL-11 could offer a new non-antibiotic approach to the management of sepsis in these patients."

He and his co-authors enrolled 40 patients with leukemia or lymphoma and randomly assigned half of the cohort to receive daily subcutaneous injections of rhIL-11 or placebo. Their primary outcome goal was a reduction in bacteremia - pathogenic organisms in the circulation. They isolated 26 infectious organisms, of which 21 (77 percent) were enteric Gram-negative or Gram-positive, presumed to have originated from the gut. The 20 placebo-control patients harbored 20 different bacterial agents in their blood, while the 20 IL-11-treated patients had only six of these infections.

Two-Hatted Gene In Blood Needed To Generate Stem Cells But Not Stemness' Of Their Function

The production of blood cells - mainly erythrocytes and lymphocytes - is sustained throughout our lives by hematopoietic stem cells (HSCs). In a recent issue of Nature, dated Jan. 19, 2003, scientists at the Harvard-affiliated Dana-Farber Cancer Institute in Boston report that a gene called SCL/tal-1 is essential for the generation of HSCs. Their article is titled: "Hematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukemia SCL/tal-1 gene."

Paradoxically, the article reports that while the SCL/tal-1 gene is essential for the generation of HSCs, surprisingly, its continued expression is not essential for HSC functions. In the gene's absence, HSCs neither die nor lose their "stemness" identity.

"The apparent stability of the HSC phenotype in the absence of SCL/tal-1 may reflect complex epigenetic circuits established in a context manner during embryogenesis," the researchers propose. Their results now distinguish two classes of hematopoietic stem cell transcription factors: those required to generate HSCs, and those needed for later HSC properties, such as long-term repopulating activity and multipotency.