by Jim Kling
(Issue 8 ? posted May 16, 1997; archived May 30, 1997)
The notion of completely destroying a cancer patient's immune system - and then "seeding" it anew with stem cells from a healthy donor - seemed odd to many cancer physicians in the 1950s. But as E. Donnall Thomas contemplated directions of cancer research while at the Massachusetts Institute of Technology during that time, the idea intrigued him. After all, mice could be rescued after a lethal dose of radiation through such a procedure. It seemed simple enough - but that was deceiving. Early attempts met with failure, and in the early sixties "some [researchers] said we shouldn't go on," Thomas recalls today. That didn't deter him, though, and in 1969 Thomas met with Seattle physician William Hutchinson - brother of local baseball hero Fred Hutchinson - to consider moving into the new facility he was planning, The Fred Hutchinson Cancer Research Center, often referred to as "The Hutch."
Founded in part with funding from the National Cancer Act of 1971, the new center opened in 1975 and "gave us much better facilities than we'd had before," says Thomas. That boost, combined with repeated trials - and with the help of advances in fundamental biology, such as improved tissue typing - helped Thomas and his team develop the bone marrow transplantation procedure that has become the treatment of choice for many leukemias, aplastic anemia, and some immune deficiencies. The center estimates its cure rate for chronic myelogenous leukemia at 75-80%, and severe aplastic anemia yields to the treatment at a 90% rate. That work earned Thomas the Nobel Prize in medicine in 1990, and it helped stake The Hutch's claim as a top-flight clinical and research center.
The center is about to see change, though, as current director Robert W. Day steps down, to be replaced on July 1 by Leland Hartwell, a geneticist who has maintained a joint appointment at The Hutch and the University of Washington since he moved from UW to The Hutch in 1996. Hartwell vows to maintain the strong research base at The Hutch, but he comes with an agenda of his own: to increase dramatically interdisciplinary research at the institute.
The timing could not be better. Over the past decade, the center has seen an expansion of its facilities to include two new buildings, occupied in 1993, that house two of the four divisions of the center, Molecular Medicine and Basic Sciences. A third, Clinical Research, will remain apart until a third building, to be complete next spring, is ready to move into, while Public Health will have to wait until a fourth phase is complete by the end of the decade. There is a general sense of anticipation toward the reunion: "None of us has been very happy about" the separation, says Thomas.
The reunion of the departments echoes Hartwell's vision. "When I was offered the directorship I figured that was a mandate that the institution wanted to [emphasize communication between the disciplines] . . . certainly if they wanted a strong administrator, I don't have a track record [as one]," says Hartwell.
Hartwell's dedication to interdisciplinary research has its roots in his own research career, one that followed a path from fundamental work in yeast cell cycle control to the genetic mechanisms that underlie human cancer. He was the first to demonstrate, in the 1960s, that the cell cycle in yeast cells is genetically controlled. He also documented the existence of cell cycle checkpoints, control mechanisms that check to see that a given stage in cell division - DNA synthesis, for example - has been completed before proceeding on to the next stage. More recently, Hartwell has suggested a role for checkpoint defects and genetic instability in cancer progression and has proposed how to exploit these defects to devise rational cancer therapies. "For over 30 years, a majority of the key insights into the cell cycle have been made by [him]," according to Mark Groudine, director of the Basic Sciences division at The Hutch.
Hartwell moved to the University of Washington department of genetics in 1968, where his yeast cell cycle work helped set the stage for an explosion in human cancer research when, in a 1987 article in Nature, Paul Nurse at Oxford University announced a surprising discovery: The human homologue of the CDC2 gene - a protein kinase that is essential to the cell cycle in yeast - would function when transfected into yeast cells that lacked the gene. Soon others confirmed that many human homologues of yeast genes perform the same functions, and a wealth of information gleaned from yeast cells was suddenly directly applicable to the study of human cell division - and cancer.
Though the discoveries were a surprise to him and most of the rest of the research world, in hindsight Hartwell says they shouldn't have been. "The metabolic pathways are all the same, why shouldn't the [signal pathways that lead to cell division] be the same." The revelation that the yeast model had so much to offer caused great excitement, but Hartwell realized the time had come to move past these simplified systems. "I came to the conclusion that human biology would only become clearer through a real combination of three disciplines: basic science, clinical sciences, and the population sciences."
Fortuitously, just across town lay The Hutch, whose strength in these disciplines made it an ideal altar for the wedding of the complementary approaches. Two sabbaticals spent at The Hutch were enough to convince Hartwell that its research divisions are top-notch, and a year ago he embarked on what he calls his "sociological experiment": dubbed by Hartwell the Interdivisional Research and Training Initiative, it called for meetings and retreats to bring these diverse disciplines together for a view of "the big picture" of cancer.
Hutch researchers were receptive. Ross Prentice, director of the Public Health division at The Hutch, welcomes the interaction. "It was refreshing to me that a senior person with a very substantial reputation as a basic biological scientist was willing to move his base to [The Hutch] and commit half of his time to interdisciplinary research program development. . . . As scientists we tend have the knee-jerk reaction that whatever we don't know about can't be important, so it takes somebody with confidence to step out and endorse the groups and areas that they are not a part of," says Prentice.
The task that Hartwell has set for himself is daunting. The center's divisions are large and diverse: Basic Sciences employs 25 faculty, Clinical Research 66, and Public Health 49. And the disciplines are separated by more than just the tools they use and the subjects they study, says Steve Collins, director of the recently formed Molecular Medicine division, which boasts a modest seven faculty members. Researchers in different fields "think differently and speak a different language," he says.
In fact, the approach championed by the Molecular Medicine division seems tailor-made for Hartwell's vision. Researchers there are applying molecular science to human disease, a broad-ranging effort that encompasses projects such as gene therapy, using genetic markers to enhance epidemiology, and antibody engineering, among others. That approach makes molecular medicine a good proving ground for combining disciplines, says Hartwell: "It is potentially in the position to make that synthesis." Collins agrees, stressing molecular medicine's unique approach: "We're using as our experimental model not a worm, not a fly, not a yeast cell . . . but [rather] human disease."
As new links are forged between the various disciplines under Hartwell's leadership, The Hutch's signature research will go on. The clinical department is considering a hundred different protocols to improve bone marrow transplantation, according to Thomas, "which means about one hundred different aspects [of the procedure] are under investigation."
One new approach, spearheaded by Dana Matthews and Fred Appelbaum, Director of Clinical Research at The Hutch, uses I-131 radio-labeled anti-CD45 antibodies to ablate the patient's immune system before the bone marrow transplant. The current protocol calls for high levels of non-selective chemotherapy or radiation, which, aside from the severe side effects they cause, may not destroy all of the malignant cells. In contrast, since the CD45 epitope occurs on 90% of all leukemias, the antibodies may be able to knock out malignancies with minimal side effects. In phase I/II studies of acute myeloleukemia patients, patients were treated with a combination of anti-CD45/I-131 antibodies with lower chemotherapy doses prior to the bone marrow transplant. As a result, patients who had already relapsed prior to the treatment had subsequent relapse rates of 25-30%, significantly lower than historical values of 50-55% obtained with the standard protocol. In patients with no previous relapse, 16 of 17 remained in remission - compared to only 55-60% of historical cases.
These were not prospective, randomized trials, stresses Appelbaum, but the results are nonetheless encouraging. "We have been very pleased with how well we've been able to translate early [cell culture and animal] experiments to man, and how many of the predictions we've made from these models have come true," he says.
Indeed, from Thomas's early predictions that transplant experiments in mice would lead to human therapy, to the yeast cell cycle control work that serendipitously impacted human cancer biology, researchers seem bent on bringing molecular forces to bear against human cancer.
Hartwell, for one, is determined: "The next thing to do is roll up our sleeves, and we'll make a real impact."
Jim Kling writes in Washington State about science and the environment. His work has appeared in Science, Nature Biotechnology, The Scientist, and Popular Science magazine's Web site.
Endlinks
The Fred Hutchinson Cancer Research Center's Web site presents the institution's resources and activities.
A virtual tour may be taken of "The Hutch."
Leland Hartwell's research page describes the work of his lab at the University of Washington.
Bone Marrow Transplantation at NIH, a National Institutes of Health page, shows its own clinical unit's activities and links to other BMT resources on the Web.
Molecular Biology of Yeast - excellent guide to literature and links on the "motor of modern molecular biology."