By Nancy Garcia
Associate Editor

A “matchmaking“ company designed to shorten the gap between new geneticdisease targets and scores of specially synthesized, small organic molecule“suitors“ is adding another star to its cast.

Darwin Molecular Corp. was formed last year with seed financing from Cetus Ronald Cape and Amgen Inc. founder George Rathmann. The Kirkland, Wash.,directed evolution company plans to announce today that David Galas, who headed the HumanGenome Project at the U.S. Department of Energy, will become vice president of researchand development.

“He's one of the most knowledgeable people in the world on DNA sequencing andmapping technology, and has the wisdom and creativity to manage scientific programs forthe best possible outcome from an organization,“ said President and Chief ExecutiveOfficer Mark Pearson, a molecular biologist who was executive director of the Du PontMerck Pharmaceutical Co.'s cancer and inflammatory disease research.

DNA Footprinting

Galas is best known for developing the DNA footprinting technique used to isolatecontrol regions bound by regulatory proteins. His challenge at Darwin Molecular will be toconvert information from human genome sequences into practical drugs.

The company will focus on regions responsible for enzymes and receptors associated withcancer, AIDS and autoimmune diseases, including multiple sclerosis, Human Genome Projectresearch grants to sequence DNA that might encode these targets could be a self-sustainingfirst step toward the therapeutic altar, Pearson said.

Sequencing should be shotgun-quick using refined gel electrophoresis and automatedanalysis pioneered by scientific adviser Leroy Hood, chairman of the molecularbiotechnology department at the University of Washington School of Medicine. The companyexpects to cut DNA processing time 900 percent within two years, then shorten the rateanother 9,000 percent over the next four years.

Quick sequencing could hasten development of drugs directed at the receptor or enzymeof interest. Average drug development now takes roughly $400 million and 12 years.

Potential Drug Leads

In the other half of the technological marriage, libraries of up to 1 million potentialdrug leads are intended to move drug development ahead a generation. Company foundersenvision creating pools of small organic molecules rather than more easily diversifiedpeptides, proteins and oligonucleotides that can cost more to mass-produce and pose morechallenges for storage and administration.

“It really turns upside down what organic chemistry has been doing for the lastcentury,“ scientific adviser Gerald Joyce, an associate professor of chemistry andmolecular biology at The Scripps Research Institute, said about directed evolution ofsmall molecules. “It's easy to make a mess.“

“It's trying to do the kind of chemistry that every good chemist learned not to doin graduate school,“ Pearson explained. “Instead of taking a substrate andtrying to get 100 percent yield with as few side reactions as possible, you're trying toget 100 molecules of 1 percent yield, or 1 million molecules of .001 percent yield.“

Protein targets, produced through genetic engineering, can be mixed into this pool ofpotential suitors, and best-binding organic molecules fished out. Next, closely relatedanalogs are sequentially screened en masse until the best match emerges.

Creating these analogs in directed evolution will either require retracing syntheticsteps, Pearson said, or using sensitive mass spectroscopy to detect likely structureswithin a mix of compounds.

“We're betting the company on the idea that small molecule combinatorial chemistrycan be done,“ he said.

Darwin Molecular plans to seek $50 million in financing during the coming year, andmove to leased facilities in Bothell, Wash.

“We're a very early-stage company,“ Pearson said, “but there's all sortsof nifty things coming down the pike.“

The company forecasts having lead compounds within two to three years, and will bringin some fees by performing sequencing for others under contract. Darwin Molecular may alsolicense in sequencing methods and university combinatorial libraries if they appearpromising. The company will also contract for new software that could recognize patternsin families of closely related genes or predict three-dimensional protein structuresthrough “informatics.“

“We're trying to push the technology envelope,“ Pearson said, “butmainly we're trying to convert molecular genome information directly into therapeutics.We're comfortable that the time is now; we've assembled a cast of characters withexpertise in sequencing, chemistry, informatics and applied evolution. We couldn't havedone this 10 years ago.“

“It's the latest wave,“ added Joyce. A handful of small-molecule directedevolution companies are already starting to spin out of academic settings, and similarprograms are also under way at larger biotechnology and pharmaceutical companies.