By Jennifer Van Brunt
Armed with a technology so powerful it is capable of providing a detailed blueprint of the genetic activity of any cell or tissue in the body, Digital Gene Technologies Inc. is on a mission to ensure that the scientific community at large can use the technology to answer some very basic questions.
The three-year-old La Jolla, Calif., company already has signed on a few high-profile corporate collaborators that wish to exploit this technology for commercial purposes, and will be announcing more corporate partnerships in the near future, according to president and CEO Robert Sutcliffe. But the privately held firm is just as intent on providing its powerful technology to academic researchers — free of charge — to give them a cutting-edge tool to dig out the answers to more fundamental biological mysteries.
In fact, Digital Gene Technologies' scientific founder, J. Gregor Sutcliffe, devised the program of academic research collaborations, together with the company's scientific advisory board. The goal is to accelerate the pace of basic research, explained Robert Sutcliffe, but it's also a way to demonstrate just how powerful the technology is. "By making its powerful and sensitive gene expression analysis system available to the scientific community, Digital Gene Technologies is fostering the concept that tools developed with help from federally supported grants, as these tools were, should be made accessible to other federally supported scientists," added Floyd Bloom, chairman of the department of neuropharmacology at The Scripps Research Institute and a member of the company's scientific advisory board.
Put another way, "Greg [Sutcliffe] wants to repay some of the basic support he has received, the support that made TOGA possible," explained his brother, Robert.
The program keeps the company closely tied to its roots. Moreover, Robert Sutcliffe said, it allows company researchers the opportunity to work hand-in-hand with first-rate academic labs. It also gives university scientists access to state-of-the-art technology that would otherwise not be available to them, whatever the cost. Academics are encouraged to publish their results — offering even broader exposure for the company and its technology.
Greg Sutcliffe, a research scientist at Scripps, in La Jolla, invented Digital Gene's technology — TOGA (total gene expression analysis) — which identifies all the expressed gene sequences, or mRNA molecules, generated within a cell. Because these messages code for the proteins that determine cellular activities, it's possible to follow the precise genetic changes over time that allow a cell or tissue to perform its particular function. The technology is so powerful that it is even able to pick out rare messages — down to the level of just one per cell — from among the very abundant, which may be present in thousands of copies. And the gene producing one protein could be just as critical to the cell as the gene producing thousands. The technology, which uses nucleotide sequences near the end of the mRNA to find the molecules, identifies them whether they were previously discovered or not. The unknown expressed sequences, in turn, can lead to new gene discoveries. "We see the expression levels of all genes present in a sample — known or unknown — at the same time. We can also watch those levels change," Robert Sutcliffe said. This goes for normal tissue, or one that is diseased, or even one that has been treated with drugs.
Digital Gene Technologies announced its first academic collaboration — with Peter Vogt of The Scripps Research Institute — in early April 1998. Vogt, head of the division of oncovirology at Scripps and a member of the National Academy of Sciences, is widely credited as the discoverer of oncogenes. Vogt and his collaborators will use TOGA to identify and isolate genes that are differentially expressed in chicken cells transformed by the oncogene jun. Vogt hopes to gain insight into the earliest stages in the initiation of cancer.
The second academic project, also announced in April, was submitted by Simon Halegoua of the State University of New York, Stony Brook. Halegoua, whose research focuses on the nerve growth factor signal transduction pathway, will use TOGA technology to help determine the full array of genes that regulate the neural actions of growth factors and cytokines.
The third project, announced in early June, involves a search for the mRNAs that are differentially expressed in rats carrying natural genetic variants for alcohol preference. The work, being conducted by Indiana University School of Medicine researchers Ting-Kai Li and Lucinda Carr, is part of an effort to identify the genetic basis of alcoholism.
Digital Gene Technologies' scientific advisory board has so far approved 10 academic collaborations, seven of which have been signed (although only three have been disclosed so far), according to Robert Sutcliffe. In general, the company retains commercial rights to molecules first highlighted in TOGA assays of project samples — even if the specific molecule is not one the researcher chooses to pursue.
The two corporate partners that Digital Gene Technologies has signed up to date are also asking some tough questions. The latest deal, with Seattle-based Immunex Corp. (NASDAQ:IMNX), centers on identifying targets for diagnosing and treating inflammatory diseases of the gastrointestinal system. If all goes perfectly, Digital Gene could receive as much as $93 million in precommercialization payments over the course of the five-year agreement, which was announced in December 1997. Immunex will use TOGA to process cell line samples in the hopes of identifying three target molecules for development.
And the agreement with the Italian pharmaceutical company The Recordati Group, signed in April 1997, centers on assessing the activity of Recordati's calcium channel blocker, Lercanidipine, against atherosclerosis. Recordati also intends to use TOGA to explore the underlying causes of atherosclerosis.
Is there a limit to the capacity of the TOGA system? Not for the near future, Sutcliffe explained. TOGA uses one robot, which can process about 6,000 samples per year. That might not sound like a lot, compared to high-throughput screening systems that claim the ability to analyze 100,000 or more samples in far less time. But 6,000 samples annually translates to 12 to 24 individual scientific projects, he continued. Since the company reserves about 20 percent of the robot's capacity for academic collaborators' projects — as well as the work of its own scientists — there still remains a full 80 percent for commercial partnerships.
The data are made available to the collaborators about 45 to 60 days after the sample is processed, according to Sutcliffe, but the actual processing time for any one sample is much shorter. The time lag comes in the way the system is set up: The mRNAs are subdivided into 256 pools based on nucleotide sequence, with about 40 different mRNAs in each pool. But different samples —say, from six separate collaborators — are batched, to make the processing more efficient. On the other hand, because each pool is so small, all the mRNAs contained therein can be separately resolved. And the mRNAs are tagged in such a way that the sequence can be immediately cross-referenced to any available database. Thus, it quickly becomes possible to ascertain what — if any — information is already available on that particular sequence. One sample might end up containing 6,000 to 10,000 genes: In the end, "you know what they're doing, and you know whether they're novel or not," Sutcliffe concluded.