Medicine and Translational Research, Molecular Biology
Boston Children's Hospital
Dr. Orkin is also David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School.
Molecular Genetics of Stem Cells
Stem cells in bone marrow give rise to about a trillion blood cells each day: red cells, which carry oxygen, and white cells, which are essential for immune responses and blood clotting. These blood cells are produced in response to growth factor signals that turn on certain genes. Since 1976, Stuart Orkin has been studying those genes and how they might be tricked into promoting cancer. “I went to medical school because I saw that the science I might want to do could relate to disease,” he says. “We’re not trying to apply all the information ourselves, but we hope that others can [use it to develop better treatments].”
Orkin’s research career began when, at 31, he was given a lab at Harvard and told to write some grant proposals, even though he had only just finished his medical residency. “The challenges to getting started were not as great as they are now,” he says. “And I was naïve enough to think that if I did what I wanted to do and had a few good people join me early on, things would work out.”
Molecular biology was born in the mid-1970s, when scientists learned how to clone genes. Even at that early date, Orkin realized that this new field might be helpful to medicine. So he brought cloning technology into his lab and learned DNA sequencing, which was also in its infancy at that time. For the next 10 years, his group worked out the molecular basis of thalassemia. People with this disease have defects in genes that encode the subunits of hemoglobin, the oxygen-carrying protein in red cells. They develop anemia and other complications. “This was the first disease for which scientists gained a nearly complete understanding through molecular biology,” Orkin says.
Currently, he is studying the switch between fetal hemoglobin and adult hemoglobin—work that may lead to better treatments for thalassemia and other hemoglobin disorders, such as sickle cell anemia. Fetal hemoglobin production begins about two months into gestation and ceases about three months after birth, when adult hemoglobin takes over. If more were known about the process, it might be possible to switch on the fetal hemoglobin genes and switch off the faulty adult ones in people with blood disorders. “So one of the things we’re particularly interested in at the moment is, what is the mechanism?” Orkin says.
Orkin has also studied white cell disorders. In 1986, he cloned the gene for chronic granulomatous disease, in which certain immune cells are unable to kill bacteria and fungi that have become entombed inside troublesome nodules. This was the first disease gene to be located when the molecular basis for the disorder was unknown. “We had a good collaborator, [HHMI investigator] Louis Kunkel,” Orkin says. “He was two floors below us, so we used to go up and down those stairs very frequently to figure out where we were in the project!”
Another breakthrough came in 1989, when the group cloned a gene called GATA-1, which encodes one of the proteins, called transcription factors, that regulate gene activity by binding to DNA. “Relatively few specific mammalian transcription factors had been studied at that time,” Orkin explains. “Part of the folklore was that they would be present at vanishingly low levels. But GATA-1 was [active] enough that our technology worked.”
GATA-1 is a master gene that regulates most of the events that produce red cells and several white cell types from stem cells in bone marrow. “We wanted to know how you make a red cell,” Orkin says. “Working backwards, we had to start thinking about stem cells.” Since cloning GATA-1, Orkin’s group has cloned nearly all the other genes involved in blood cell differentiation.
The GATA-1 studies sparked the group’s interest in a type of leukemia that develops only in babies with Down syndrome, which occurs when there are three copies of chromosome 21. This unusual leukemia results from mutations in GATA-1. “What is it about the genetic constitution or the regulatory network of the cell that [ties these mutations to Down syndrome]?”
Although this work must be done in cell cultures rather than in mice (which cannot be given entire human chromosomes), the group has developed several mouse models for other types of leukemia. And branching out from their blood studies, they recently developed a model for osteosarcoma, the commonest and most lethal bone cancer. “We’re trying to understand how the cancer cells metastasize and whether there are pathways that we could block that would kill the cells, differentiate them, or prevent them from metastasizing,” Orkin says.
This mouse work relies on HHMI funding. “All the animal facilities in the Boston area are very expensive,” Orkin says. “These experiments would be virtually impossible without HHMI’s support.”
Despite his long list of achievements, Orkin is surprised every time an experiment succeeds. “One of the things about doing research is that you are only as good as the last experiment. There is always a sense that you may never be able to do it again. But somehow it seems to happen.”