Bulyk searches for DNA on-off switches

Martha Bulyk held what looked like an ordinary glass slide up to the large window that is much of one wall of her Harvard Medical School office. The slide seemed to be blank, but a puff of breath exposed row after row of tiny dots, appearing like the hidden writing of a secret message.

But the dots are more decoder ring than secret code, an array made up of bits of DNA that Bulyk is using to understand mysterious proteins called transcription factors that are critical in understanding DNA because they turn individual genes on and off.

“I’m interested in understanding how it is that the genome is organized,” Bulyk said. “We get such complex life forms and processes and all the instructions are included in the genome somehow.”

Bulyk, assistant professor of medicine, of pathology, and of health sciences and technology at Harvard Medical School, has pioneered the use of microarray technology in the analysis of transcription factors. Her advance promises to dramatically cut the time needed to characterize transcription factors and their associated genes from weeks and months to just a day.

Her work, published in December 2004 in the journal Nature Genetics, won her recognition from the Massachusetts Institute of Technology’s Technology Review Magazine, which listed her among the top 35 technology innovators under age 35.

“Martha has been a pioneer in assays for DNA-protein interactions and the computational analysis of the resulting large data sets,” said Harvard Medical School Genetics Professor George Church.

Scientists have long known that the blueprint of life is contained in DNA – long, double-stranded helical molecules in the nucleus of every cell in our bodies. DNA itself is made up of a series of base pairs, whose order determines everything from eye color and hair color to number of legs and body shape.

The encoded genes are put into action through a process called transcription, where a special enzyme breaks the DNA strands apart, reads the code, and creates an RNA molecule that carries that code elsewhere in the cell to be translated into action. The transcription process itself is regulated by proteins that bind to specific DNA regulatory elements on either side of the gene. It is these proteins, called transcription factors, and their DNA binding sites that have caught Bulyk’s eye.

In her work with the microarrays, Bulyk and her lab team first created microarrays by dotting bits of DNA onto glass slides and then exposed the arrays to a possible transcription factor. They knew that a transcription factor would bind to the DNA at specific sites, and so they gently washed the chip to remove protein that wasn’t bound. The remaining proteins, which had been tagged with a fluorescent molecule, glowed. To find what they were looking for, all the researchers had to do was look for the glowing dots.