"From bench to bedside" is a short phrase, but the time it takes basic research to truly change patient care is often measured in decades. Many basic researchers never see the clinical fruits of their efforts. Owen Witte has.
In the late 1970s, as a new postdoc in David Baltimore's lab at MIT, Witte characterized a protein produced by a gene from the Abelson virus, which causes leukemia in mice. The protein results from the fusion of the viral gene with a mouse gene.
Several years later, the Philadelphia chromosome—a fusion of chromosomes 9 and 22—was fingered as the cause of chronic myelogenous leukemia (CML) in humans. Witte, now at UCLA, discovered that human CML cells produced a larger version of the fused Abelson/mouse protein. Further work made it clear that the human protein also resulted from two fused genes: BCR and ABL (the human form of the Abelson gene).
Witte identified BCR-ABL as a tyrosine kinase, a protein that can transfer a phosphate group to the amino acid tyrosine. Tyrosine kinases are important in controlling other enzymes. BCR-ABL's structure allowed it to circumvent the usual methods that cells use to regulate tyrosine kinases, leading to uncontrolled cell growth.
Scientists knew that if they could find a way to stop BCR-ABL, they could treat CML successfully. In 1996, a compound called STI571 was found to bind to BCR-ABL and paralyze it. Brian J. Druker (HHMI, Oregon Health & Science University) and Charles L. Sawyers (HHMI, Memorial Sloan-Kettering Cancer Center) were instrumental in conducting clinical trials of ST1571. The first trial treated 31 CML patients, and all had complete remissions.
In 2002, the U.S. Food and Drug Administration approved STI571, now called Gleevec (imatinib). The drug is now used to treat CML and certain types of rare gastrointestinal tumors, with minimal side effects.
The results of Witte's research didn't hit home until he talked to CML patients who had received Gleevec. "As a physician and scientist, I couldn't imagine a more inspiring event," he said. "You want to continue, and do more."
Witte is doing more. His lab discovered the gene for Bruton's tyrosine kinase (BTK), which plays an important role in B cell maturation. A loss of BTK function leads to X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (XID) in mice. People with XLA, and mice with XID, do not make mature B cells or antibodies; they are prone to serious infections and sometimes die from them.
In 2004, with researchers from the University of Washington, Witte's group introduced a working BTK gene into the hematopoeitic stem cells of XID mice. This normalized the immune response and restored normal B cell development. BTK is an active target for drug discovery, with potential applications for lymphomas and autoimmune disorders.
After discovering the gene for BTK, Witte and colleagues wanted to study the entire immune systems of XID mice over time. "We were frustrated because there were no techniques for how to do this," he said. "I started thinking about how we could look inside from outside the body and monitor immune function."
Witte turned to a scaled-down version of positron emission tomography (PET) called microPET. The resolution of standard PET wasn't fine enough to image mice, so UCLA researchers Simon Cherry, Sanjiv Gambhir, and Michael Phelps adapted PET for small-animal imaging. Witte's group has used the technology to follow labeled immune system cells over a period of weeks as they respond to a solid tumor. They've also shown that a radiolabeled substance used to monitor glucose metabolism, FDG, also can be used to track immune response and inflammation.
Human applications of PET are many, varied, and astounding. "Say you had a therapy that you thought might work against an autoimmune disease, an antibody or small molecule. If you treated animals with it, you would have to sacrifice them to see their tissues. Using this technology, you could follow what's happening over time."
Using PET in clinical trials would maximize the knowledge researchers could gain from each patient. "The more you can learn from each person, the faster you will know if you've got a good drug or not." Recent work from his group defined a new PET probe called FAC to monitor immune activation and certain cancers.
Witte also studies the biology of prostate cancer development and metastasis. His group identified stem cell–like populations that help maintain the prostate. They have found two pathways that regulate prostate stem cells and at least one pathway that leads to cancerous growth.
"I think it reenergizes you to try something new," he said. "But I was only able to make these transitions because I had HHMI support."
Witte also has the support of his wife, Jami McLaughlin, both at home and in the lab. Married since 1984, the two have worked together almost as long.