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DARPA Seeks a Few Good Microarrays To Meet Challenges of Biodefense

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What’s a handshake worth? If it’s a handshake with one of the program managers of the Defense Advanced Research Projects Agency (DARPA), it might be worth millions of dollars in funding.

To be sure, millions of federal tax dollars won’t necessarily flow into a microarray commercialization project based on one conversation, but it’s a way to begin the funding process, said Alan Rudolph, program manager in DARPA’s defense sciences office.

“We are much less formal than most federal agencies,” Rudolph said last week after giving the final keynote address of the Chips to Hits Conference in Philadelphia. In front of a capacity audience, Rudolph spoke specifically about the agency’s role in nurturing microarray technology for national security applications. The agency, like other defense programs, has been pressured by the events of 9/11 and afterwards to accelerate its discovery program for tools and procedures that mitigate biowarfare and other potential terrorist acts.

A process that begins with personal contact is not an encouraging thought for entrepreneurs. At least, in the commercial arena, one has potential suitors in the form of hundreds of VCs who exist solely to invest others’ funds. The federal government, not counting Congress, of course, has far fewer funds disbursers. The project managers at DARPA, the Department of Defense’s equivalent of a venture investment agency, do have authorization to personally make funding decisions, said Rudolph. The agency has a budget that is expected to grow to $2.7 billion for fiscal year 2003 from $2.4 billion in 2002.

“The best way to start is to have a personal dialogue with a program manager,” Rudoph said. “We do have RFPs or broad agency announcements and competitions for large amounts of money. But, unlike NIH or NSF, simply putting in paperwork is often not sufficient.”

DARPA has, however, invested substantially in microarray technology. Xeotron of Houston in February said it won a $3 million DARPA grant to develop an array-based oligonucleotide synthesis system to assemble up to 10,000 base pairs of DNA within 24 hours.

In 2001, Agilent Labs signed a $6.1 million, three-year gene synthesis research agreement with DARPA and the University of Colorado; and Orchid BioSciences of Princeton, N.J., inked a three-year, $4.8 million contract to develop technology for microfluidic-enabled DNA synthesis that could yield “significant quantities” of long oligos.

“We invest in the long-term, high-risk kinds of technologies that could serve existing applications as well as future visioned applications,” Rudolph said.

He said the agency is earmarking “a couple of hundred million dollars a year of funding for the life sciences.” The agency likes to invest in project areas, bringing to bear mass resources with the aim of quickly producing a prototype or proof of principle and then handing off the results to others, outside the government, for commercialization, he said.

Life Sciences Initiatives

DARPA is currently funding initiatives to create “microarray kinds of interfaces that can actually plug into the organism- and system-level understanding of things,” Rudolph said.

That means programs such as one that uses cells from the brightly colored scales of a Siamese fighting fish - which change color depending on the water content - for a microarray application as a potential water biosensor; or another project to create microarrays to place in bee hives to analyze environmental samples gathered by the busy little insects, who, on a daily basis, may range as far as five kilometers from their honeycomb.

The agency researches creatively and, because its task is defending the United States, it has to find solutions that have fault tolerances far more stringent than allowable in commercial usage. Also tools must bring results, quickly.

“No one tool can be useful, it’s likely that a whole consort of tools can be brought to bear,” he said. “We are trying to get away from one box solves all problems.”

Pathogen Progress

In the biowarfare defense area, the agency is funding the use of DNA arrays to build signatures of the exposure of pathogens like anthrax. The agency is undertaking gene response profiling, marking genes sustained and upregulated or downregulated — over time — to identify unique patterns associated with pathogens. These libraries will be used with the goal of quickly taking information from an unknown sample and matching it against the stored data.

In addition to trying to find the gene expression profiles that signify exposure to particular pathogens, agency-funded projects are also searching for antibodies and changes in metabolism that would signify a particular pathogen response, and have invested in efforts to identify the pathogen itself. Projects seek to identify nucleic acid or protein content within a sample via rapid sequencing or sequence recognition.

“We are making some progress,” he said. “The challenges of creating a unique signature of a biological agent purposely perpetrated by a terrorist is a very, very difficult problem.”

The agency is seeking methods that would eliminate amplification and speed sequencing — “full genomes in hours to days,” he said. One of the firms the agency has invested in is VisiGen Biotechnologies, a spinout from the University of Houston that has received $147,000 in 2002.

The agency has also expanded funding for a basket of other investments, from arrays that go beyond DNA analysis to cell arrays and tissue arrays, brain arrays, neural tissue arrays and liver arrays for toxicology evaluations as well as one project that Randolph described as a lung-on-a-chip. In that technology, already in the prototype phase, a bioactive glass is seeded with lung-type cells growing on optical fibers to sense for respiratory pathogens.

Taking technology Out of the Lab And into the Field

DARPA’s microarray tools aren’t always designed for the benchtop, Randolph said. It may be in a small tent in an environment like the arid region of Afghanistan. “Supporting these kinds of environments present unique challenges to us,” he said.

The agency is about to produce a freeze-dried platelet, in late-stage pre-clinical safety and efficacy testing, and has its eyes on doing the same with red cells and, later, freeze-drying nucleated cells.

In conjunction with GeneExpert, the agency is producing a cartridge that can allow multiplexing PCR.

Hello Washington, We’ve Got an Systems Problem

The biggest problem DARPA has is how to integrate all of the biodefense inventions that it has funded. The Department of Defense knows how to create systems that defense contractors can integrate into things like a tank or an aircraft. However, that’s not the case with biotechnology, Randolph said.

“We have a large system-integration problem,” he said. “There is no BioBoeing. We can go through things like sample preparation, building a chip for a microarray with a desired component — molecular, cellular or tissue — but we need a way to create longevity and stability that will allow us to deliver it to the market; in our case, out in the field. We are looking to build bridges to make these things realizable.”

This too could be a funding opportunity started with a hello and a handshake.

Randolph’s message was heard by the crowd in the Philadelphia Marriott. After he spoke, a couple of dozen audience members lined up for a handshake.

— MOK

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