Biochemistry, Molecular Biology
Massachusetts Institute of Technology
Dr. Bell is also a professor of biology at the Massachusetts Institute of Technology and assistant molecular biologist at Massachusetts General Hospital, Boston.
Duplication of Eukaryotic Chromosomes
After fertilization, cells in a developing human embryo continually divide to form billions of cells—and the adorable baby that eventually bounces on your knee. Each cell contains the same genetic information because each strand of DNA's double helix inside the nucleus of every dividing parent cell makes a copy of itself. The two duplexes then segregate into the daughter cells. Cell division in tissues continues throughout life.
"Clearly, replicating DNA is vital to an organism's survival," says biochemist Stephen Bell. Fascinated by the duplication process, for almost 20 years Bell has been studying the machinery cells use to maintain the integrity of DNA replication. Among his many discoveries are the identification of proteins that initiate copying and the determination of their functions at a molecular level.
When Bell started analyzing DNA replication in the early 1990s, scientists knew a lot about bacterial and viral DNA duplication. But Bell's discoveries are in eukaryotic organisms, such as humans and yeast, that have their DNA in discrete chromosomes inside a membrane-bound nucleus that is separate from the rest of the cell. (Microbes, or prokaryotes, do not segregate the DNA away from the rest of the cell and they replicate their DNA a bit differently.)
Bell loved science in high school, and he became further enamored by biochemistry as an undergraduate in the 1980s. In his first weeks of biochemistry class, the professor described how biochemistry enables scientists to isolate individual biological molecules and to understand how the molecules function in the cell. Bell quickly realized how much remained to be discovered about the cell's many biomolecules. With so much unknown, he saw that this was an area where he could make a contribution. "It was then I decided to become a biochemist," he says.
Hooked on biochemistry, he did his Ph.D. in the laboratory of Robert Tjian (now HHMI president) at the University of California, Berkeley. For his thesis, he studied the factors that influence the enzyme RNA polymerase I to initiate transcription of ribosomal RNA genes. Ribosomes, consisting of ribosomal RNA and proteins, are the protein-making machinery in cells. How polymerases, with other proteins, determine the DNA region to begin making an RNA transcript is a key issue in biology. Bell identified two proteins that help RNA polymerase I find the ribosomal RNA gene and allow it to be transcribed.
After graduate school, Bell, who wanted to add genetics to his scientific repertoire, did a postdoctoral fellowship with Bruce Stillman at Cold Spring Harbor Laboratory. There he used yeast, a model organism amenable to genetic manipulation, to study protein factors and DNA sequences involved in DNA replication, a process he has been investigating since.
At the time, Bell and other scientists hoped to simulate in a test tube the replication of yeast DNA. Test tube, or in vitro, studies allow scientists to purify proteins involved in biological processes and determine their molecular activity. The challenge for Bell was to replicate yeast DNA.
In the process of looking for events associated with the replication of yeast DNA, Bell identified a complex of six proteins, called the origin recognition complex (ORC), that bind to specific regions on the yeast chromosome when replication begins. These DNA sequences are called origins of replication. Although he was not looking for this protein complex, it had long been sought and he immediately recognized its importance. He succeeded, where others had failed, because he put into the reaction mixture certain chemicals others hadn't thought to add.
Identifying ORC allowed Bell and others to understand how the components of the complex work and how other proteins act with them at the onset of DNA replication. But many fundamental questions about DNA replication remain under investigation. Bell's Massachusetts Institute of Technology laboratory is examining, for example, how the MCM complex, an enzyme that unwinds the DNA helix before replication occurs, is recruited to the start sites of replication. His lab is also studying how the activation of the MCM complex is triggered at just the right time. Another mystery is how the cells in higher eukaryotes, such as humans, begin replication, because they lack the distinct origins of replication that yeast have.
Bell says he is still as excited about uncovering the mysteries of DNA replication as he was in his first biochemistry class. "I tell people when they come to my laboratory that their work could end up in a basic biology textbook because so much about DNA replication in higher organisms is unknown," says Bell, who co-authored the widely used textbook Molecular Biology of the Gene. "So much more about replication still needs to be learned."