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Chip-Making, Harvard-Style

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By John F. Lauerman

In 1997, Harvard toxicologist Leona Samson sent a postdoc to Santa Clara to participate in an Affymetrix user program. She thought the experience could help her lab get “ahead of the game” in its studies of yeast’s response to DNA damage. She was right: Early last year, Samson dropped a bombshell in her field when her data showed that expression levels in about one-third of the S. cerevisiae genome change significantly after damage from alkylating agents.

Now, Samson’s team is trying to stay ahead, and possibly save money, by making its own microarray chips. In Samson’s sixth-floor laboratory in a nondescript Harvard School of Public Health high-rise known simply as Building 1, 29-year-old postdoc Thomas Begley is amplifying each of the yeast’s 6,200 genes and cross-linking them to lysine-coated slides.

With starter information from websites like Stanford biochemist Pat Brown’s Mguide, consultation from fellow scientists, and an initial investment of about $115,000 for a GMS 417 printer to dot chips with cDNAs and a matching scanner to read them, he hopes to make chips for several dollars apiece.

What’s more, Begley plans to design chips that will allow Samson to closely monitor MAG-1, a DNA-repair gene that responds strongly to damage from alkylating agents, and other genes that are coregulated with MAG-1.

Rather than pay $1,000 for commercial oligonucleotide arrays, a growing number of public-sector labs are churning out their own. The capability lets them better focus on their own research questions and cut costs along the way. Genomics centers at Harvard and elsewhere make and distribute microarrays to labs throughout their systems, while some labs — like Samson’s — try to make their own.

Begley avoided buying thousands of oligonucleotides for his PCR reactions by using universally primed yeast genes. But the chip-making process, which he’s estimated would take three of the lab’s 11 members six weeks of full-time work under the best of circumstances, has nonetheless been slowed by unforeseen problems. During printing, the solution buffering Begley’s cDNAs evaporated. Logistical problems, such as tight freezer space in the cramped, dated lab, became roadblocks. He now hopes to finish by March 2001.

“You really have to stay focused,” he says. “Nothing is fast, and we run into all the problems you would expect when you scale up procedures.”

Begley is aware that his own chips will read gene expression levels somewhat differently than the commercially available models the lab has been using, and no doubt quite differently than chips made in other labs.

It could be an advantage to have chips with more sensitivity in certain dynamic ranges. On the other hand, having chips that are more or less unique could hurt his experiment’s reproducibility. The Harvard Genome Research Center is planning an effort to compare and standardize readouts from different types of chips, including homemade microarrays, but currently there’s no universal yardstick.

“It’s basically a lot of people feeling their way forward,” observes Harvard geneticist George Church, who routinely makes his own chips, and has given Begley advice. “Having your own chips can mean having access to more technology, but in practice it can also give you more distractions.”

 

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