When Orion Genomics started its work in DNA methylation five years ago, research possibilities were as vast as the plant kingdom it focused on. Now, using a technology based on methylation work at Rob Martienssen’s Cold Spring Harbor Laboratory, Orion is expanding its territory even further. Chief among potential applications such as biodefense, bacteriology, and infectious disease work, according to CEO Nathan Lakey, is trying to understand cancer.
Orion’s original technology improves gene discovery in plants. “The whole plant kingdom seems to organize its genes in compact little sections,” Lakey explains. “We can get rid of junk DNA and not interrupt the continuity of a gene.” By eliminating the junk — that is, any methylated part of the plant’s genome — the critical parts of the genome remain and are easier to find and catalog.
In 2000, Martienssen’s lab began using microarrays to study methylation profiles in Arabidopsis. Two years later, Orion brought that concept in-house and has since been gearing up for commercialization. The idea seems simple: separate genomic DNA into two buckets, methylated and not, and then compare their profiles.
Research has shown that methylation could be a prime indicator of early stages of cancer — genes that are aberrantly methylated (silenced when they shouldn’t be or not silenced when they should be) appear to contribute to the onset and rapid growth of cancer. The trick is that in all other respects, these genes look perfectly normal. “Genes that are supposed to be expressed, instead of being mutated or deleted, are present and they look to be wild type,” explains Jeff Jeddeloh, Orion’s leader of strategic genetics. “But they’re not only not expressed, but highly packaged and almost always tend to be highly methylated.” It’s a dream opportunity for Orion, which has spent years honing its expertise in the area.
Lakey adds, “What has been shown is that in some patients who have cancer, one can find little traces of erroneously methylated DNA in blood serum.” That opens the door for finding key biomarkers which could then be developed into a non-invasive, early-detection cancer diagnostic. Other strategies for measuring RNA, proteins, or metabolites rely on indicators that vary a great deal between cells, Lakey points out. “What we like about DNA is it’s normalized in each cell.”
Scaling up the new technology, MethylScope, has been a challenge. Martienssen proved the concept on a genome 20 times smaller than the human sequence. Also, for cancer applications, Orion can expect just trace amounts of DNA to work with, compared with the greenhouses of potential DNA samples available for plant research.
Now, Orion faces its next hurdle of getting this to customers. It’s still too early to sell it in a box — it “requires substantial expertise to practice well,” Lakey acknowledges — so he’s looking to form partnerships instead.
And as Jeddeloh points out, the technology isn’t the solution. If MethylScope succeeds, it will locate a number of biomarkers critical for the early detection of cancer; building diagnostics around that is another story altogether, though Orion is already busy developing that kind of assay.
But it’s a start. And Lakey appreciates the new opportunity for Orion. “As a company, we focused on a field that at the time didn’t seem that sexy,” he says. “Where was DNA methylation back in 1998? Overall it wasn’t getting the attention.”
— Meredith Salisbury