Microbiology professor makes strides after discovering the use of umbilical cords to treat cancers
April 19, 2016
"I was driven because I loved what I did," Hal Broxmeyer says. "When things work out, you want to work more."
Over a 32-year career at the IU School of Medicine, Broxmeyer, a native New Yorker and IU professor of microbiology and immunology, conceived, developed and proved the utility of using once-discarded blood from umbilical cords to treat blood and bone cancers. Over the last three decades, physicians have collected blood from cast-off cords, frozen it, thawed it and infused it into patients more than 35,000 times.
Call up Broxmeyer's name in a database that sifts through research journals, and it pops up more than 1,100 times. Scan faces of past presidents of the American Society of Hematology, and there's Broxmeyer -- the only non-physician to ever lead the group.
Broxmeyer's tenacity and love for his job are undeniable, and his age doesn't seem to have slowed him down. Nor have two fights with thyroid cancer deterred him from seeking to answer a single question: Can we make cord-blood transplants better?
With Broxmeyer focused on the matter, the answer is yes. In June 2015, he and the seven investigators working in his lab unveiled a major finding in Cell, one of the world’s most prominent scientific journals. In September 1988, Scott Cooper, the laboratory's de facto manager, had belted a tank into a seat on a transatlantic flight to Paris. Inside, liquid nitrogen cooled the air to negative 283 degrees Fahrenheit to carry five ounces of blood more than 4,000 miles. In an isolation ward at Hospital Saint-Louis, a 5-year-old boy named Matthew Farrow awaited their arrival.
Since age 2, Farrow had suffered from Fanconi anemia, a disorder that left his bone marrow unable to generate blood cells to ward off infections, ferry oxygen or clot wounds. Matthew's prognosis had been grim. An older sister failed as a potential match to provide bone marrow, and his parents weren't optimistic that the National Marrow Donor Program registry would better their son's odds.
In 1987, the Farrows conceived a third child and hoped the baby's marrow could one day match with Matthew's. But a scientist from the IU School of Medicine would offer an unconventional solution: hematopoietic stem cells.
Imagine hematopoietic stem cells as miniature blood factories operating deep within our big bones. The assembly line never shuts down, churning out red and white blood cells, platelets, and more stem cells. Broxmeyer and fellow collaborators had proved through laboratory studies that umbilical cord blood was a viable source of hematopoietic stem cells, and that the liquid harbored enough cells to equal what could be culled from bone marrow.
Still, most of Broxmeyer's peers dismissed the notion that cord blood could be used in place of traditional bone marrow transplants. Assuaging skeptics meant proving cord blood's utility in patients. The Farrows' unborn daughter lacked the genotype for Fanconi, and her tissue was a near-identical match to Matthew's. In February 1988, Dorothy Farrow was born. Blood was drawn from her umbilical cord and shipped to Broxmeyer's lab at IU.
Several months later, the Farrows jetted to Paris, where European protocols allowed the procedure to take place. Ultimately, it fell to Cooper to deliver the blood to the physician who had agreed to perform the transplant. Broxmeyer followed behind a week later.
On October 6, 1988, the blood from Dorothy Farrow's umbilical cord flowed from an IV into her brother. Broxmeyer flew back to the States and spent a nerve-wracking three weeks waiting to see if the procedure worked. "It was very scary because it took Matthew a long time," he said. On Day 22, the boy's blood count came back normal. Two months after the transplant, Matthew Farrow had received his final blood cell transfusion, and his B-positive blood had changed to O-positive—the same as his sister's.
Three decades later, the procedure is reliable. Often, administering cord-derived stem cells to rebuild a patient's obliterated immune system takes less than 15 minutes. Blood can be stored for up to 25 years, giving rise to a blood-banking industry that one estimate predicts will generate $15 billion in revenue by 2019. And success rates using cord blood mirror those of bone marrow.
But questions still nag Broxmeyer and other researchers. The procedure is most common, and successful, in children. How can we ensure there are enough cells to treat adults? Can you boost the number of cells available? What would help those stem cells home in on marrow and engraft themselves? And how can the financial burden -- it can cost upwards of $40,000 for a single unit of cord blood -- be slashed to remove another hurdle for patients?
Roughly five years ago, Charlie Mantel, a longtime member of the lab, had a hunch. He wondered: How does a stem cell behave in normal air? Typically, the oxygen level in bone marrow ranges between 1 percent and 4 percent. This is five times less than the air we breathe. Exposure to normal air, Mantel thought, might tax the cell. To cope, a stem cell evolves, becoming a progenitor cell in a process the lab dubbed EPHOSS: Extra Physiologic Oxygen Shock Stress.
So Mantel pitched Broxmeyer an idea: Gather the stem cells in low oxygen.
"Let's go for it," Broxmeyer replied. "Let's test it."
At the time, Mantel and the lab had only done very preliminary experiments investigating how EPHOSS affected stem cells in cord blood. Then Heather O'Leary, a postdoctoral researcher, joined the team, and she and Mantel began collecting cells from the femurs of mice, processing them and then plating them in a setting with only 3 percent oxygen. Their early data was promising: It showed that low-oxygen conditions could net larger colonies of cells. But the project was hampered by the fact that the lab didn't own a hypoxic chamber, the piece of equipment scientists use to regulate oxygen levels in a test environment.
A year later, an alumnus of the lab based in South Korea agreed to buy the group a proper chamber to test the oxygen levels. With the right apparatus and the same procedure, the impact of EPHOSS was clear. "Collecting cells in ambient air, you actually get fewer stem cells than there should have been," Broxmeyer said.
A routine took hold. When a mother who agreed to donate her child's umbilical cord underwent a Cesarean section, a pager would buzz. O'Leary and Cooper would trek to Eskenazi Hospital to collect the cord and transport it back to the lab, extracting the blood using the same process they had with bone marrow from mice.
The outcome followed the same line: You could triple the number of stem cells if they weren't exposed to normal air.
"We look at that not as an end, but as a beginning of how cells are really functioning in the body," Broxmeyer said. "The key is, 'Can we take this work to the next step? Can we make cord blood transplantation better? Can we make other stem cell things better?'"
One thing is for certain: Only a lone circumstance will impede him from keeping up his work. "Only death," he says with a grin, "is going to stop me."