The Gargantuan Task of a Tiny Fish
words by barbara hurley / photographs by john emerson
his is a fish story. But one in which the size and importance of the fish don’t need to be exaggerated because they are instruments of innovation with immeasurable promise for the future treatment of cancer.
They are one-inch zebrafish, whose transparency enables researchers like Hatem Sabaawy to see how specific mutations cause tumors and ultimately how those tumors respond to certain drugs. The fish have been for some time the source of research on organ development, but more recently have been used to model human disease. Their blood is similar to human blood, their reproduction is prolific, and their genome is almost complete and very available, making comparative genomics easier. And when you see the 15,000 fish housed in a small space at The Cancer Institute of New Jersey, you understand that their small size is an additional plus.
Sabaawy’s medical specialty is hematology, which, with a doctorate in gene therapy, led to an NIH fellowship that combined stem cell therapy and cancer research using the zebrafish. His work centers around stem cells, specifically cancer stem cells, also called tumor initiating cells. These cells create the bulk of the tumor, appear resistant to current chemotherapy and are likely responsible for the regeneration of malignancies.
The fish turned out to be the perfect models for Sabaawy’s research. He created transgenic zebrafish by altering their genetic material with a common mutation found in leukemia patients. In a few months the fish have leukemia, and researchers can see and better understand how the cancer develops. Of course, the ultimate goal is finding the agent that will eliminate emerging tumor cells and facilitate tumor cell death, apoptosis.
Sabaawy has taken a giant step closer to that goal with the enhancer genetic screen. The screen examines the blood of leukemia patients to develop a specific genetic signature to identify mutations in each individual. He is receiving samples from all over the world and targeting common mutations, which are being passed on to the zebrafish that will become testing grounds for new drugs. In addition, he is working with Joseph Bertino, MD, associate director and chief scientific officer, CINJ, Robert DiPaola, MD, director, CINJ and a New Jersey company (PTC Therapeutics) on a process that isolates cancer stem cells from a patient’s tumor cells. When these human cells are transported into the zebrafish, a tumor grows and the fish become live incubators for testing the various therapeutic agents — new drugs — that will be most effective for that particular patient. Such is the potential of truly personalized medicine, and the work has already started, Sabaawy reports, with prostate cancer. He is “hopeful that the zebrafish research will lead to new therapies to treat hematologic malignancies and solid tumors and eventually have implications for other serious diseases.”
Wearing “another hat” as the Director of the Production Facility for Cell and Gene Therapy (cGMP facility), Sabaawy also reports on an innovative collaboration in regenerative medicine between UMDNJ-Robert Wood Johnson Medical School, Cairo University Medical School, where he trained, and the NIH to study the potential of adult stem cell therapy for spinal cord injuries. In a clinical trial in Egypt, bone marrow stem cells from the injured patients themselves were used therapeutically with some success in a majority of the 80 participants. “Patients weren’t rising from wheelchairs to run marathons,” he explains, “But a young male paraplegic can now walk with a walker. Another man can walk with the aid of two canes.” Of the original cohort of patients, most have seen improvement and 25 are now walking. Bringing this stem cell therapy to the U.S. is dependent on FDA approval of the cell therapy product, which acts like a drug and therefore must undergo rigorous regulatory scrutiny. Sabaawy is motivated — and optimistic. .