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Botstein takes a big picture approach to genetics

Every cell carries a vast library of information, handed down from parent to child and stored in a person’s DNA. This genetic information determines whether a person has dimples, a thumb that bends backward and a hairline with a widow’s peak. Genes also influence a person’s risk of contracting diseases, such as breast cancer.

David Botstein has devoted his life to decoding this genetic code, and on Jan. 31, the renowned geneticist and a leader of the Human Genome Project presented his research at Lehigh University.

Students, professors, staff and even local high school biology teachers gathered in Whitaker 303 to attend his free, public presentation. The day before, Botstein gave a technical lecture on the coordination of growth rate, cell cycle, stress response and metabolic activity in yeast. His visit was funded by a grant from the Howard Hughes Medical Institute (HHMI).

President Alice P. Gast introduced Botstein as a “pioneer” in interdisciplinary sciences. “I know David as a significant force behind the scenes at Princeton and at M.I.T.,” she said. “He is a highly revered and well sought-out thinker.”

Between 1900 and 1960, scientists learned how the body stored inherited information, he said.

“They were figuring out how the tape recorder works,” Botstein said, often pointing to or touching the large screen displaying his slides as he described the history of modern genetics, beginning in the 1900s up to his own cutting-edge research.

During the first six decades, scientists unraveled the twisted ladder, known as DNA, to find genetic information encrypted in its rungs. Like the tape in the tape recorder, DNA is the physical medium that carries information. Genes are stored in DNA, similar to songs recorded on a tape. These genes act as blueprints, instructing the body on how to make proteins—the body’s basic building blocks. A human’s genetic “album,” called the genome, contains over 20,000 genes total, said Botstein.

Although every cell in a person’s body will contain identical genetic information, no cell uses all of these genes. For example, blood cells use, or express, different genes than skin cells.

Scientists compare whole genomes

Until recently, the only way to compare genes expressed in a blood cell to those in a skin cell was to examine each of the 20,000 genes individually.

“It’s a problem worse than doing what Google has to do by hand,” Botstein said.

Now, two technologies, the mircoarray and the computer, allow scientists to examine entire genomes as a whole, said Botstein, whose research involves both.

To determine which genes are active, Botstein uses a device called the microarray, which looks like a small “Connect-the-Dots” game board. Tiny round wells in the microarray are filled with individual genes and are arranged by vertically by gene and horizontally by experiment—such as location in the body.

Botstein and his team of researchers inject the wells with a dye that causes active genes to appear redder, while those inactive genes appear green.

The results are then programmed in a computer that uses a logarithm to organize the data, grouping cells based on overall gene activity.

“The idea is not to do a large number of individual observations but to look at the whole picture—at patterns of gene expression,” Botstein said.

Reaching “a new level of assessment”

The ability to group cells based on gene activity can be particularly useful to those interested in tailoring medicine to an individual, as Botstein demonstrated with his work on inherited breast cancer.

Botstein and his team of researchers compared the genomes in cancer cells taken from women with two types of inherited breast cancer. Although mutations in either the BRCA1 or BRCA2 gene can increase a woman’s chances of developing breast and ovarian cancer, the resulting cancers respond to medicine differently, said Botstein.

Women with breast cancer caused by a BRCA1 mutation have a lower survival rate than those without any mutations. However, these women responded better to chemotherapy than did women without the mutation. In contrast, women with a BRCA2 were just as likely to survive as those without a mutation and may not respond as well to chemotherapy, Botstein said.

By using the microarray and the computer, Botstein learned that BRCA1 cancer cells expressed very different genes than BRCA2 cells.

“They are probably as different as lung cancer is from breast cancer,” said Botstein. The different mutations represent “different diseases.”

With this technique, doctors can better diagnosis breast cancer. Because they are examining thousands of genes at once, they have reduced their risk of statistical error compared to testing individual genes.

Furthermore, doctors can tailor cancer treatment to the specific mutation, treating women with a BRCA1 mutation with chemotherapy while considering other methods of treatment for women with BRCA2.

“The clinical uses are better diagnosis, better detection, new targets and monitoring,” said Botstein. "The genome and computer have allowed us to reach a new level of assessment."

At Princeton, Botstein is director of the Lewis-Sigler Institute for Integrative Genomics and oversees the Center of Excellence in Complex Biomedical Systems Research, established by the National Institute of General Medical Sciences, part of the National Institutes of Health. He has long been a proponent of interdisciplinary approaches to major problems in the life sciences, and his research integrates quantitative methods, physics, and computational science.

Botstein is leading a team of faculty who are teaching a new experimental introductory science curriculum, where the basic ideas of physics, chemistry, computer science and biology, along with the relevant mathematics, are taught together.

--Becky Straw

Posted on Monday, February 04, 2008

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