Life in the blood
By Matthew Harris
On a slow afternoon in early July last summer, Hal Broxmeyer was counting. The longtime professor of microbiology and immunology hunched over an Olympus CKP-TR microscope. Peering down its binocular tube into a well, his 70-year-old eyes scanned small clusters of cells before he lifted his head to scrawl digits in a column on a sheet of paper.
Scoring cell colonies is as rudimentary as bench research gets. It’s also a task veteran researchers tend to cede to newbies in their lab’s employ.
Few would dispute Broxmeyer’s right to hand this task off. Over a 32-year career at the IU School of Medicine, the native New Yorker 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.
So why does Broxmeyer, a researcher at the IU Simon Cancer Center, engage in counting cells, the most elementary of tasks? “It kind of relaxes me,” he said.
And the trusty, if battered, Olympus remains his instrument of choice. Forty years ago, a mentor gifted it to Broxmeyer. Now, its gray paint is nicked, and a crack splits the glass plate on its stage. Nostalgia as much as utility keeps him from ditching one of the few items he packed up before decamping from Memorial Sloan Kettering Cancer Center in 1983. “It’s a pretty crummy one,” Broxmeyer said. “But it’s all I need.”
And it sates a ravenous curiosity. Age has not weathered Broxmeyer’s tenacity. 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.
So why stop? Broxmeyer and his microscope have revelations to share.
First you need a history lesson about the genesis of cordblood transplants. To help, Broxmeyer stores an artifact in a cubicle across the hall from his office. Big Boy, he calls it. And the moniker is apt for a dry-shipper—a cross between a propane tank and Igloo water cooler—meant to keep its contents locked in a deep freeze.
In September 1988, Scott Cooper, the laboratory’s de facto manager and Big Boy’s roommate, belted the tank into a seat on a Trans-Atlantic flight to Paris. Inside, liquid nitrogen cooled the air to minus 283° Fahrenheit to ferry 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 waited for it to flow into his veins.
Inelegantly put, the child was a beta test. And Broxmeyer has held on to the relic that made it possible. “He’s hoping the Smithsonian will want it someday,” Cooper said.
Since age 2, Farrow had suffered from Fanconi’s 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 the National Donor Marrow 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.
Imagine hematopoietic stem cells as miniature blood factories operating deep in our big bones. The assembly line never shutters, churning out red and white blood cells, platelets and more stem cells. Broxmeyer and fellow collaborators proved through laboratory studies that 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.
“We had to pick a disease there was some good hope for,” Broxmeyer said. Their choice: Fanconi’s Anemia. The rest of the story unfolds perfectly. The Farrows’ unborn daughter lacked the genotype for Fanconi’s. Her tissue was a near identical match to Matthew’s. In February 1988, Dorothy Farrow, whose name meant “gift from God,” 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 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 for 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, his blood count came back normal. Two months after the transplant, 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? 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, then 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.
This differentiation matters. Hematopoietic stem cells are like a Kinko’s that never closes, capable of copying themselves infinitely. A progenitor, though, can only replicate a limited number of times. By collecting cord blood in normal air, perhaps physicians were losing stem cells needed for a transplant by unwittingly causing them to become progenitor cells.
So Mantel pitched Broxmeyer an idea: Gather the stem cells in low oxygen.
“Let’s go for it,” Broxmeyer replied. “Let’s test it.”
Early in his career, Broxmeyer didn’t decompress. After long days at Sloan Kettering, he’d descend into the underbelly and commute along the rumbling innards of New York’s subway. The jostling car was a mobile office, one where he meticulously plotted out experiments.
During the next day’s trek, he’d digest data and start composing abstracts in his head.
““I was driven because I loved what I did. When things work out, you want to work more.”Hal Broxmeyer, Ph.D.
“I was driven because I loved what I did,” Broxmeyer said. “When things work out, you want to work more.”
When he first arrived at IU, the marching orders were clearly defined: If there was open space at the bench, a researcher should be sitting there.
“He was just tenacious,” said Cooper, one of Broxmeyer’s first hires upon arriving in Indiana. “He could probably see before all of us where this was going to open up a new field.”
Broxmeyer frames his ascent up the ranks as a product of skill and timing. In the late 1980s, Dr. Joseph Walther, himself a professor of medicine at the school, had money from the sale of Winona Memorial Hospital and used some to set up the Walther Oncology Center. He asked Broxmeyer to head up its research arm—a job he held until 2009. Over the same span, he led the Department of Microbiology and Immunology.
Prolific is the attribute most often pinned to him. In his tenure at the IU School of Medicine, it has been his routine to publish 25 papers a year. Quantity doesn’t rob those investigations of quality, either. His work has graced the high-impact pages of Science, Nature Medicine, Blood and the New England Journal of Medicine. This corpus is as influential as it is ample. Peers have cited its contents more than 27,000 times.
“Hal is a force of nature,” said Dr. Patrick Loehrer, who is director of the IU Simon Cancer Center and who joined the medical school faculty in 1983 with Broxmeyer. “He works with one speed—fifth gear. He’s never off.”
It’s a quality evident outside the sedate confines of his laboratory, as well.
Growing up, Broxmeyer realized he loved weight lifting on its own merits more than he did for its original purpose—cross-training track. No, it’s not a hobby. There’s a full Olympic weight set in his basement. He’s won the USA Weightlifting Federation master’s division—twice.
Give Broxmeyer five minutes to dig through his hard drive for a PowerPoint. He’ll pull up a presentation packed with grainy photos from his youth. There he is with a head of curls and Buddy Holly glasses clad in a singlet. His jaw is clenched, torso angled forward and a strained bar loaded with iron plates hoisted above his head.
Learning moderation involved veering into excess. There was the time he tried to run 100 laps on a track—in searing 98-degree heat. Why? Just to see if he could. It took a passerby telling Broxmeyer no one would be around to pick up his body after he collapsed to end the attempt. Or there was his endeavor to complete a 20-kilometer race around Central Park. His training regimen? Clipping off a brisk two miles a day for two weeks. “I almost died,” he said. “They had to hospitalize me.” He paused a beat. “But I finished.”
A Reply to Heather O’Leary’s e-mail hit her inbox faster than she expected. It was 2011, and O’Leary was wrapping up a doctorate at West Virginia University and casting about for a post-doctoral fellowship. She’d studied how leukemia behaves in bone marrow, but wanted to learn more about normal blood cell development, a process called hematopoiesis. She’d dashed off a message to Broxmeyer, hearing his lab might mesh with her interests.
“I am going to call you in 20 minutes,” Broxmeyer wrote.
At the time, Mantel and the lab had only done very preliminary experiments investigating how EPHOSS affected stem cells in cord blood. Once O’Leary joined the team, she and Mantel would collect cells from the femurs of mice, process them and then plate 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 their findings were also hit or miss.
The problem was they did their work in the mechanical equivalent of a plastic bag. To mimic the low-oxygen environment, like the one in bone marrow, scientists use a hypoxic chamber. It’s a sealed plastic box where you can regulate how much oxygen is present in air. And the lab didn’t own one.
So Mantel, a longtime protein chemist, improvised using materials like PVC pipe and plastic lining. He cut armholes in the front, along with an air lock. A hose ran across the lab from a large tank to pump in nitrogen.
“It was really like somebody tinkering in their garage,” Cooper said. “There was nothing pretty about it.” To work, a researcher would slide his arms into dishwashing gloves and be duct-taped into the apparatus. And even then, the oxygen level would fluctuate, sometimes to twice the ideal level.
A year later, an alumnus of the lab based in South Korea agreed to buy the group a proper chamber. With the right apparatus and the same procedure, the impact of EPHOSS was clear. “Collecting cells in ambient air, you actually get less stem cells than there should have been,” Broxmeyer said.
The finding was interesting, but not enough to pique the interest of editors at a journal like Cell. They had to show it held true in humans.
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?’”
The first sign that something was wrong was mostly innocuous: A slow tightening at the base of his neck. Then there was the routine checkup, followed by a scan, then the biopsy. In late 2013, the diagnosis was handed down. It was thyroid cancer. Yet Broxmeyer fretted more about outsiders’ perceptions of his condition than his own health. He worried long-standing grants—some stretching back to the mid-1980s—wouldn’t be renewed. There were papers in press that he didn’t want languishing on an editor’s desk. “He was worried his value might decrease,” Cooper said.
So he only told five people outside the lab. While he recuperated after surgery in January 2014, he didn’t want his name on the door. He only missed a week of work. “Everything was hunky-dory,” Broxmeyer said, “except they missed some in my voice box.”
Late last year, a thyroglobulin test came back high. The cancer had invaded his vocal cords. Endocrinologists told him another surgery would require sacrificing his voice. A vocal prosthesis could be installed. Speech therapy would be necessary. A quarter-sized hole near his throat is a scar he accepts matter-of-factly. “No sense worrying about it now,” he said.
“If something tries to kick him, you can bet he’s going to kick back,” said Dr. Randy Brutkiewicz, who was recruited by Broxmeyer as an assistant professor in 1997 and rose to his current role as the IU School of Medicine’s associate dean for graduate studies.
Ceding his administrative roles and tussling with cancer helped crystallize Broxmeyer’s focus now as he oversees his laboratory. “He’s psyched,” Brutkiewicz said. “It’s just that simple. He’s having fun.” The ramifications of EPHOSS still have to be worked out, but Broxmeyer is clear in framing how wideranging they might be, spreading beyond the mere application to cord blood.
If personalized medicine is to move forward, creating a world where therapies are tailored for each patient, it involves removing cells from the body to look at what genes they express. “What if the cell is different, even a little bit, from how it is in the body?” he asks. “You’re not really learning what’s going to happen when you try modulating it with therapy.”
A lone circumstance will impede him from keeping up his work. “Only death,” he says with a grin, “is going to stop me.”