HARVARD GAZETTE ARCHIVES

Martha Bulyk: 'I'm interested in understanding how it is that the genome is organized.' (Staff photo Rose Lincoln/Harvard News 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.

Bulyk's work was published last December in the journal Nature Genetics.

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.

Once the transcription factor's DNA binding sites were identified, researchers had to carefully analyze the DNA to understand its sequence and gain clues to its function.

Bulyk's work in that paper used genes and transcription factors from yeast, which are far simpler than humans and other higher life forms. Bulyk said that over 200 different transcription factors are at work in yeast cells, while 1,500 to 2,000 different proteins are functioning as transcription factors in humans.

Life in a water droplet

But for the life in a drop of pond water, Bulyk may never have tread this career path.

Bulyk said she became interested in biology when she was 12, crediting a science teacher who showed her the teeming microscopic life within a drop of pond water.

From there, Bulyk said, she became fascinated with the processes that make life work. She graduated from a suburban Philadelphia high school and attended the Massachusetts Institute of Technology, graduating in 1993 with twin bachelor of science degrees in biology and math. She earned a Ph.D. in biophysics from Harvard in 2001.

Bulyk did her doctoral work in Church's lab and worked there for a short time as a postdoctoral fellow after graduating. She started her own lab later in 2001, and has been working to illuminate the behavior and nature of transcription factors ever since.

"She has continually innovated throughout her student days to today," Church said, "seeing DNA chips, not just as static receptors for labeled RNA but as synthetic resources, as multi-substrates for a variety of enzymes, and dynamic arrays of molecular machines."

Some of her more recent work focuses on the transcription factors at work in particular kinds of cells. Working with embryonic fruit flies, in collaboration with Associate Professor of Medicine Alan Michelson, Bulyk is trying to understand how combinations of transcription factors make a particular cell behave as it does. Specifically, she is looking at how a fly embryo's mesoderm cells develop into muscle cells.

The approach, while it will prove useful in understanding fruit flies, may prove applicable to humans as well, Bulyk said.

"We can apply the same approach to other organisms and cell types," Bulyk said. "We're trying to apply this kind of analysis to human gene expression."

alvin_powell@harvard.edu

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