Helping the body fight back against cancer
Immune system research promises to boost a variety of developing treatments
As a college student, William Murphy had two interests: working with children and science. He was a camp counselor and runaway shelter volunteer while earning his teaching certificate and dreaming of becoming a physician. Then he was accepted to graduate school. It was while studying immunology at the University of Texas Southwestern Medical School in Dallas that Murphy became enamored with basic cancer research. He abandoned plans to become a physician.
“You can create anything as a scientist – even a cure for a previously incurable disease,” says Murphy, an expert in the immunology of stem cell transplants who recently joined the UC Davis faculty as a professor of dermatology.
Murphy is inspired by the creativity it takes to do cutting-edge science and finds UC Davis to be the perfect place for his laboratory creations to become fully realized therapies.
“Having top-notch clinician collaborators and world-class facilities like the ones at UC Davis are crucial for advancing the kind of research that will lead to major breakthroughs,” he says.
Murphy spent his postdoctoral years and early career at the National Cancer Institute (NCI) in Bethesda, Md. After 12 years and becoming director of basic research at NCI-Frederick in Maryland, he joined the faculty at the University of Nevada, Reno (UNR) – a cross-country move prompted by his late father-in-law’s poor health.
"Understanding the complex immunology of cancer will lead to better means of preventing and treating it."
— William Murphy
“We were able to spend nearly three years caring for him,” says the husband and father of four.
Now, the Murphy family – and the Murphy laboratory – are again on the move. Murphy is currently dividing his time between UNR and UC Davis. The move of laboratory personnel will be complete by early summer. The family’s move will wait until his two eldest children graduate from high school.
1. A cancer cell among other cells
2. Natural-killer cell links to the cancer cell
3. Cancer cell "skeleton"
Murphy and his team are working on ways to better engage the body's own immune-system defenses — like natural-killer cells — to selectively attack tumors. Part of his research focuses on activating natural-killer cell protein receptors to recognize specific proteins on the surface of cancer cells. When the two molecules link, it triggers a signal leading to the death of the cancer cells.
Murphy’s recruitment fits well with plans to broaden the dermatology research program to tackle a host of health problems related to the immune system, given that the skin is an important defense against immune system invaders and often the first organ to express immune system issues.
“He is a highly respected researcher, and we are thrilled to have him on our team,” says Fu-Tong Liu, chair of the UC Davis Department of Dermatology. “We are confident he will strengthen our investigations in the areas of skin diseases, tissue regeneration, cancer and inflammation.”
Because of the broad impact of Murphy’s hire, Liu was joined by leaders from the stem cell program, internal medicine, the cancer center and the dean’s office in working diligently to bring him to UC Davis.
For the cancer center, Murphy’s arrival comes at a time when expertise in immunology is needed to help advance today’s most promising cancer treatments.
“The immune system can both fight cancer and promote it during chronic inflammatory conditions. Understanding the complex immunology of cancer will lead to better means of preventing and treating it,” he says.
“Dr. Murphy is a world-renowned immunologist who is already contributing significantly to a broad range of cutting-edge, patient-centered research at UC Davis,” Nolta says. “We are particularly excited about his work to target and kill cancer stem cells, which can remain and metastasize following chemotherapy for some aggressive tumors. It is imperative for our patients that we find new ways to kill these malignant cells, and Bill’s expertise is already helping greatly in that mission.”
Dan Longo has been a Murphy collaborator for 18 years. Longo, the scientific director of the National Institute on Aging, one of the institutes at the National Institutes of Health, describes Murphy as a world leader on the influence of hormones on the immune system.
“Although a number of clinical applications are being made from his work, his careful analysis and definition of the cellular basis for certain disease processes has also shed light on basic mechanisms of disease,” he says.
Longo praises Murphy for working to make his laboratory research relevant to the treatment of disease in humans.
“His work is distinctive for its sophisticated use of animal models of disease, which generally mimic clinical situations more closely than purely cell-line studies,” Longo says.
Murphy’s recent work has focused on the role of the immune system in stem cell transplantation, formerly called bone marrow transplantation. First used to treat blood cancers, the procedure is also used today for diseases such as aplastic anemia, immune deficiency disorders and some solid tumors.
The problem is that stem cell transplants don’t always work and, sometimes, cause new diseases. Murphy is credited with discovering the cellular mechanism behind the failure of transplanted stem cells to take up residence in bone cavities and replace immune system functions – a process called engraftment. His work suggested promising ways to enhance engraftment that, Longo says, may make it possible for cord blood to be used in adults as a source of stem cells, making donor – or allogeneic – transplants much safer.
Cancer and immunotherapy
Murphy also pioneered the treatment of cancer using stem cell transplants for immunotherapy.
“Tumors have developed elaborate ways of depressing the immune system,” Murphy explains. “The immune system also naturally turns itself on and off. This puts the body at a disadvantage when battling a chronic condition like cancer.”
The goals of cancer immunotherapy, he says, are to inhibit the ability of tumors to depress the immune system, keep the immune system from turning itself off and stimulating it to destroy tumor cells. Immunotherapy treatments can be used directly or can be combined with existing treatments to improve outcomes.
One area of immunotherapy that Murphy has been working on involves natural-killer cells, which attack tumor cells, virally infected cells and other infectious agents. He has been working on a way to use activated natural-killer cells to improve the results of stem cell transplants.
“We found that transferring natural-killer cells can provide significant anti-tumor effects while at the same time reducing the odds of rejecting the grafted cells,” he says.
Natural-killer cells can also reduce the incidence of graft-versus-host-disease, which results when donor cells mount an immunological attack on the recipient’s tissues and organs. The condition is one of the biggest hurdles to more widespread use of stem cell transplants. As scientists develop new stem cell-based therapies, preventing graft-versus-host will become increasingly important.
Currently, Murphy has four NIH R01 grants and is on a program project grant with M.D. Anderson Cancer Center looking at ways to improve the efficacy of immunotherapy in a variety of cancers. His team has so far shown that certain drugs sensitize tumors to attack from immune system cells produced by the graft, while another given immediately following a transplant reduces the incidence of graft-versus-host.
“The goal is to decrease graft-versus-host disease while improving graft-versus-tumor effects,” says Lisbeth Welniak, a project scientist who has been with Murphy since his days at the NCI. “We’re trying to get better at killing the tumor cells, while at the same time reducing the attack of the immune system on the host.”
This is one of the first projects Murphy and his lab team will tackle at UC Davis, pending approval of animal-use protocols and renewal of the initial NIH grant. The next step, Welniak says, is to expand and improve on the previous drug findings.
“We’ve had promising results in mice,” she says. “Now we need to translate those into effective therapies to use in patients.”
A new team and community player
Murphy says UC Davis is the perfect place for the scientific interactions that can bring his basic and preclinical research in graft-versus-host disease and cancer immunotherapy to their full potential for patients. To speed that process for cancer patients, he has launched a cancer inflammation research group together with Reen Wu, professor of cell biology and human anatomy, and Natalie Torok, assistant clinical professor of gastroenterology and hepatology.
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“The supportive, collegial environment at UC Davis makes it a real joy to do work,” Murphy says. “That kind of collaborative spirit is essential as science moves away from principal investigator-centered research to team-based approaches required by the most complex challenges facing science. If you have to do everything yourself in today’s science world, you’re not going to be competitive.”
According to Robert Wiltrout, NCI’s director for cancer research, Murphy’s new colleagues are bound to benefit from his perspective.
“When you talk to him, he comes up with thoughts and ideas that make your project better. Murphy is also open to suggestions that make his own work better. He is a real catalyst, one of those people with whom you really want to collaborate,” Wiltrout says.
One of the ways Murphy brings balance to his scientific work is through his ongoing commitment to kids in need. In Maryland and Reno, he served on a foster care review board and as a court-appointed volunteer investigating cases of abuse and neglect. He plans to volunteer with Sacramento CASA (Court Appointed Special Advocates for Children) once his move is complete.
“It’s very rewarding to help those who don’t otherwise have a voice,” he says. “At the end of the day, it really puts the ups and downs of academic research into perspective.”