Treating Patients

A Stem-Cell-Boosting Drug Goes to Clinical TrialIsaac Adatto, lead research technologist, feeds brine shrimp to some of the hundred thousand Zebrafish in the Zon lab.

On the second floor of the Karp Family Research Laboratories, humid rooms with wall-to-wall tanks house hundreds of varieties of tiny zebrafish, some as small as specks. In all, there are about 10,000 tanks and 200,000 fish, bred to help scientists study disease.

Several years ago, the ancestors of some of these rapidly-breeding fish helped hematologist Leonard Zon, MD, Director of the Stem Cell Program at Boston Children’s Hospital, discover a way to help patients with cancer. Zon’s team placed tiny zebrafish embryos into laboratory dishes—five fish to a well, 48 wells to a plate. The fish were bathed in more than 2,500 different test chemicals—in the hopes that at least one chemical would increase their numbers of blood stem cells.

Zon had long sought a treatment to help patients recover their immune function more quickly after chemotherapy or bone marrow transplant. Currently, when patients can’t find a suitable marrow donor to replenish their blood stem cells, the only other option is umbilical cord blood. But the number of blood stem cells in a single cord often isn’t enough for older children and adults, and using two cords increases the risk of immune complications.

“Two cords go into a person and their immune systems are different, because they come from two different babies,” Zon explains. “The immune systems start fighting each other.” Cords are also expensive and in limited supply. Could a drug be found that would help blood stem cells multiply and eliminate the need for a second cord?

The zebrafish on the second floor provided an excellent platform for answering the call. The embryos can take up chemicals through their skin, and because they’re transparent, their blood stem cell numbers can be easily counted under the microscope. Before long, they gave Zon and former research fellows Trista North, PhD, and Wolfram Goessling, MD, PhD, a potent “hit.” A derivative of prostaglandin E2 (PGE2), originally developed to fight stomach ulcers but then abandoned, boosted blood stem cell formation three- to four-fold. As reported in the Journal Nature in 2007, PGE2 helped both adult zebrafish and mice recover their blood cell populations after injury.

“We weren’t specifically looking for prostaglandins,” says Zon. “This was a surprise finding.”

Because PGE2 is already approved by the FDA for other uses, the drug moved swiftly to testing in patients. In May, 2009, a Phase I clinical trial of PGE2 began at the Dana-Farber Cancer Institute and Massachusetts General Hospital, led by Corey Cutler M.D., M.P.H., of Dana-Farber and sponsored by Fate Therapeutics.

12 adults undergoing treatment for leukemia or lymphoma received blood stem cells from two donor umbilical cords, one of which will be pre-treated with PGE2. In 10 of these 12 patients, the treated cord preferentially engrafted. This suggested that the PGE2 was active in helping blood stem cells to engraft. Recently 48 patients were treated in a Phase II clinical trial.

PGE2 is a first-of-a-kind discovery in several ways. Previous studies, including one from Zon’s own lab, had found ways to boost formation of blood stem cells, none of them lent themselves to broad medical use. PGE2 is the first small-molecule drug found to induce stem-cell production, the first drug discovered using zebrafish to go to clinical trial, and the first drug discovered through stem cell research to reach patients. Interestingly, PGE2 also seems to stimulate regeneration in other tissues, such as the liver.

Prostaglandins are known to be released by the body when inflammation is present—such as after an injury—and may be among the compounds that aid recovery. “So it makes some sense that prostaglandins would have the ability to enhance regrowth of cells,” Zon says.

Zon is internationally recognized for his work in identifying the genes that direct stem cells to develop into more specialized blood or organ cells. He directs the trans-NIH Zebrafish Genome Initiative, which he helped organize after establishing his own lab in 1991. At the time, he was studying another factor that boosts blood stem cell development, called GATA-1.

“For eight years I worked first in the mouse and then the frog, to determine how GATA-1 was induced in embryos,” Zon recalls. “Then, a number of events converged to take me in a different direction. At a conference, one of my competitors suggested that zebrafish might be a good system for understanding the genetics of stem cell regulation. Then, a scientist who had expertise with Antarctic fish asked to join my group, and a friend from Harvard called with a zebrafish mutant that couldn’t make blood, to ask if I wanted to work on it.”

Zon is also keenly interested in using zebrafish to find cancer stem cells, motivated in part by his mother’s death from breast cancer. He is among a growing number of scientists who are viewing cancer as a stem cell problem: Many tumors seem to have a subgroup of cells that are able to divide and multiply, giving rise to new cancers when transplanted into different animals. In zebrafish, Zon has been able to model melanoma to learn more about how the cancer metastasizes and the role of these stem-like cells.

But Zon has a passion other than zebrafish and stem cell research: he’s played trumpet since the age of 9, and has performed with the Longwood Symphony Orchestra since its second concert in 1984 along with dozens of other Boston medical professionals. In college he played seven hours a day. “I knew there were people who were better than I was, and I knew I wanted to pursue medicine,” Zon says. “But I’ve always taken music seriously—it’s a great hobby because you actually get better as you get older.”



  • Meet Leonard Zon, MD

    Leonard Zon, Director of Children’s Hospital Boston’s Stem Cell Program, is internationally recognized for his pioneering work in the fields of stem cell biology and cancer genetics. A Howard Hughes Medical Institute (HHMI) Investigator, he is founder and former President of the International Society for Stem Cell Research and Chair of the Executive Committee of the Harvard Stem Cell Institute (HSCI).
    Read an interview with Zon in the HHMI Bulletin.

  • Making more of your marrow

    Leonard Zon, MD, discusses the use of PGE2 to increase blood stem cells in umbilical cord blood in this video.

  • See-through fish reveal how transplants “take”

    While transplants of blood-forming stem cells help cancer patients rebuild healthy blood, some transplants don’t “take,” for reasons unknown. Now, researchers at Children’s Hospital Boston have created a zebrafish whose skin is transparent—allowing scientists to directly observe how transplanted stem cells migrate to the bone marrow, engraft, and build new blood. Read more.

  • Zon takes to the stage to help fight cancer

    After speaking about the role of embryonic stem cell research in developing cancer therapies, Zon performs the Albinoni concerto for piccolo trumpet with the Longwood Symphony Orchestra during a 2008 London fundraising tour called Artful Innovations in Cancer Care.