As Dr. Keith Loeb rides the elevator to and from his Seattle Cancer Care Alliance office, he can't help but look around at his fellow passengers and pick out the ones who have the telltale signs of cancer. He tries to imagine which patients might match the biological samples he examines in the SCCA's Pathology Lab.
Whether it's the bald little girl in her mother's arms or the gaunt man heading to another chemo appointment, Loeb is motivated by his daily witness of the human side of cancer. Those encounters propel him to work even harder as he analyzes patients' blood and tissues and drives his scientific research on genetic instability and cancer.
Loeb's professional path to this point is a picture of patience and perfection, having spent 26 years in school and training. After completing his medical and doctoral degrees at the Medical College of Wisconsin, he did his residency at the University of Washington, followed by five years as a postdoctoral fellow in the Center's Basic Sciences Division and a return to the UW for a hematopathology fellowship.
"I'm excited to be back at the Hutchinson Center," said Loeb, who joined the Clinical Research Division faculty last January. "It seems like I'm in the perfect place to follow all of my research interests. The Center is an intellectual incubator, and it's a good environment for collaboration."
Loeb is enthusiastic about returning to research he began as a Center postdoc in 2000, when he worked with Drs. Jim Roberts, Bruce Clurman and Stephen Friend. Loeb's postdoctoral work led to the creation of a mouse model that expressed a stabilized form of cyclin E, a protein whose role Roberts had discovered. Cyclin E is a key regulator responsible for promoting cell-cycle progression into the S phase, when DNA synthesis or replication occurs.
Loeb's efforts showed that misregulation of cyclin E can promote genetic instability and cancer, helping to explain why the over-expression of this protein in many cancers is predictive of more aggressive disease.
New avenues for research
An unexpected development in Loeb's mice represents another tantalizing avenue for further research. The mice developed massive spleens, 20 times larger than normal. The spleens had levels of cyclin E 50 times higher than usual. Loeb believes the mice may be good models for myeloproliferative disease, a group of disorders characterized by an overabundance of blood cells.
Loeb is working with another former Center postdoc, Northwestern University's Dr. Alex Minella, to further understand the mouse model. "As red blood cells mature, they usually stop dividing. But for some reason, the premature red blood cells in these mice developed a block in maturation," Loeb said. "Alex showed that these early-stage red-blood cells from the mice were all in S phase. It was one of the most amazing results I've ever seen — it was so clearly black or white." The researchers hypothesize that the stabilized cyclin E prevents cell maturation and instead triggers DNA synthesis.
From these mouse studies, Loeb hopes to apply what he's learned to better characterize human myeloproliferative and myelodysplastic processes (disorders where blood stem cells mature abnormally) as precursors to acute myeloid leukemia. "It would be interesting to know if cyclin E plays a similar role in blood stem-cell disorders," he said.
He is currently working on flow cytometry-based studies with the Clinical Research Division's Dr. Jerry Radich, who studies myeloproliferative and myelodysplastic disorders, and the UW's Dr. Brent Wood, who runs one of the nation's most sophisticated flow-cytometry labs next door to Loeb's office on the top floor of the SCCA building.
In a technique called phosphoflow, the researchers use antibodies specific to signaling proteins to monitor the cells' response to growth factors or drugs. Other applications of phosphoflow include detection of minimal residual disease and drug sensitivity. "In the new era of targeted therapeutics, phosphoflow will provide a quick, functional assay to determine therapeutic efficacy in blood disorders," Loeb said. They hope to identify new markers to better detect low-grade myelodysplastic disorders or to monitor the progression of myeloproliferative disorders, such as chronic myelogenous leukemia.
An inquisitive mind
"With Brent's lab having such enormous capacity, I'm really interested in collaborating on more phosphoflow translational research with other scientists here," Loeb said.
The other half of Loeb's work life is spent monitoring blood samples from SCCA bone-marrow transplant patients for signs of engraftment, residual disease, infections and graft-vs.-host disease, as well as providing his expert opinion for outside patients seeking consultation. He finds this pathological work compelling. "We get some fascinating cases," he said of his view through the microscope. "We see things most people would never see in a lifetime. It is particularly exciting to see how extensive malignancies resolve following transplantation."
Loeb isn't content with the status quo in his pathology work either. "I would like to develop better methods to detect and monitor minimal residual disease and better define the processes that lead to graft-vs.-host disease," he said.
Dubbed "Mr. Science" by his grade-school peers, Loeb has long been scientifically inquisitive. "I have a good sense of intellectual curiosity," he said. "I always ask, 'Why?'" Loeb's eagerness to learn may be credited in part to his scientific family; his father and wife are UW scientists.
Despite the family leanings, Loeb isn't pressuring his two daughters, ages 7 and 11, to pursue scientific careers. But he can't help sharing his enthusiasm for the subject. "I go over science pretty heavily with them," he said. "Last year, I went to their schools and brought a whole smorgasbord of different organs. It was a big hit."
Just like the engaging scientific setting he tries to create for his children, Loeb is excited to find himself in an ideal place for both his clinical and basic-science work. "As a research-oriented hematopathologist, the Center's focus on novel therapies and translational research targeting blood diseases provides a great combination of unique specimens and an intellectually stimulating environment," he said.