One summer night in 1967, Dr. Rainer Storb and Dr. Bob Epstein sat, feet up, on a bench in the 10th-floor laboratory on top of Seattle’s Beacon Hill and watched the sun set over the Olympic Mountains in the distance.
The scientists were depressed.
Their three-member University of Washington research team, headed by Dr. E. Donnall Thomas, was convinced that bone marrow transplantation could cure not only blood cancers, like leukemias and lymphomas, but also immune deficiencies and blood disorders by replacing patients’ faulty blood stem cells with healthy ones from a donor.
Most other cancer researchers had, by then, given up on transplantation. Early experiments in mice had not translated well to humans, and the problems of graft rejection and other immunological complications seemed insurmountable to many. Undeterred, Thomas’ research group was trying to work through the technique’s challenges in laboratory models. By that night, however, they had hit a major snag.
“We were desperate,” Storb recalled. The team had just finished a study that tried to map the inheritance of molecules called tissue antigens that indicate to the immune system whether a particular cell is “self” or “foreign.” For transplantation to work, they suspected, they had to match these antigens as best as possible between transplant donors and recipients to minimize harmful immune attacks.
But their data were hopelessly messy. They couldn’t track the antigens at all.
“We were about to throw (it) all down the sink,” said Storb, now 80 and the head of Fred Hutch’s Transplantation Biology Program since 1980. “We’d had enough.”
But sometimes, one has to come to the edge of defeat before another way is revealed.
As the lights of the nighttime city winked on below them, the two scientists began to talk through their work.
That’s when they decided they ought to see if they could do just one more experiment. And as it turned out, that’s when everything started to change.
Shaped by childhood
As a boy growing up in Essen, Germany, Storb liked to create his own toys, including a fully electrified railway system that he and a friend built in the basement of the Storb family home. He was often bored, he said, by the playthings he got as gifts.
“I’m good only up to a certain point following other people’s recipes,” Storb said.
But Storb’s childhood was rooted in the realities of World War II. In 1941, as Allied bombs began falling on his hometown, his parents sent him hundreds of miles away to a boarding school in the remote Bavarian Alps, for safekeeping. He was 6 years old.
During just his second visit home, the city burned around him every few nights as the bombs fell, and the flames were echoed in his nightmares as he slept. He didn’t come home again until Germany and its allies had surrendered.
For a boy who loved the outdoors, the school offered not only respite from the terror of firebombs, but also exciting opportunities for skiing and mountaineering. But homesickness lay over the adventure like a heavy shroud.
Outside of yearly visits from his mother and his two trips back home for Christmas, his only connection to his parents was their letters. By the last months of the war, the German postal service had disintegrated, and letters from home stopped coming.
Ducking bullets
One day, in April 1945 when Storb was 9, he was in a field near his school when Allied fighter planes flew into the valley, so low that he could see the pilots’ faces. The machine gunners shot indiscriminately — for fun, he thinks — and he dove under a fence, waiting to die. He still remembers the smell of the tall grass in his nostrils.
“I thought this was it,” he said.
The fighter planes made two more passes over the field before they flew away.
Six months later, Storb returned home to his parents and to a city half-destroyed by more than 270 firebombing raids.
It was just the third time that the now–10-year-old had seen his father since he was evacuated. During the war, Dr. Werner Storb, a civilian physician and Great War veteran, had been consumed with his responsibility for his patients, not only those in his own clinic, but also the patients of doctors who had been drafted or fled to the relative safety of the countryside.
Werner Storb had followed his own father, a surgeon, into medicine.
As life slowly returned to normal and young Rainer grew up, the inveterate tinkerer imagined becoming an engineer instead.
But without any role models in the field, Storb didn’t know how to pursue that goal.
So the young man decided it would be easiest to follow the path of his father and grandfather before him and to try a career as a doctor after all.
That casual adolescent decision eventually helped to change the world of medicine.
Out of failure, the first successes
In the early 1960s, Storb was working in a basic research laboratory in Paris when he began hearing about Thomas’ pioneering transplantation research — which eventually earned Thomas the Nobel Prize in Physiology or Medicine.
The sense of wonder and possibility inherent in the new field drew Storb to the U.S. in 1965. He had to be a part of it.
“It’s spectacular, when you think about it,” Storb said. “You can irradiate and then put in new stem cells — it fascinated me.”
But most importantly, he was excited by the chance that this research offered him to make a direct impact on lives.
“For me, the important thing was — and that’s why I left Paris, actually — was to do something I could apply to patients,” he said.
And so, that summer evening in 1967, as the twilight glowed in the Seattle lab, Storb and Epstein decided to talk through their failed experiment.
In those years, the scientists were struggling to make their greatest leap — the translation of transplantation from preclinical models into humans — and this was one of many experiments of those years that did not work out as planned. At those frustrating and desperate times, the team was forced to back up, rethink and try again.
“I spent a lot of time walking and thinking,” Storb said. “That’s one of the hardest things, to learn out of your failures.”
The frustration with this particular experiment arose from the fact that the tools the scientists possessed to look at antigens were primitive and did not always yield the black-and-white, yes-or-no answers for which they were looking.
As Storb and Epstein rehashed their work that night, they decided to take a different tack: Instead of simply mapping all of the antigens to a family tree as they had tried to do, the scientists would use only the clearest tissue-type matches and mismatches to carry out transplants in laboratory models and then watch what happened. It would take a long time and it would be difficult, but they believed it would show them the path forward toward making successful transplants in humans.
So they did.
It took two more years of preclinical research in laboratory models of transplant, but the experiment worked: Storb, Epstein, Thomas and their colleagues proved that success requires pre-transplantation tissue-typing — at the time, a cumbersome effort — to find a matched donor. They also showed that it is important to suppress a patient’s immune system after transplant to allow the new cells to take hold.
Transplantation, they felt, was finally ready for patients.
In 1969, a man in his 30s with end-stage leukemia received the team’s first-in-human transplant. And the transplantation field, which once seemed like a dead end to many, started coming back to life.
None of the six patients the team transplanted in that first year survived. But while each death affected Storb and his teammates, these first transplants taught them how to make better matches between patients and donors, despite the primitive tissue-typing available at the time.
In this time, Storb says he never lost faith that transplants could succeed as a way to cure cancer and noncancerous diseases of the blood and immune system.
“We carefully looked at every nook and cranny of the (preclinical) experiments to try to understand the biology. And once you had an understanding of the experiment this way, that way and the other way, you had the feeling that this should work in humans,” Storb said. “It gave me an enormous amount of confidence. That’s what my confidence rested on, was the experimentation. All of that I did with my own hands.”
Beginning the following year, patients started surviving, even though their diseases were considered incurable and transplantation still experimental. Over the years, more and more patients lived as the scientists continued to improve the therapy.
Today, more than 1 million transplants have now been performed worldwide. The technique has transformed the survival rates for some conditions from nearly zero to over 90 percent and is considered standard of care for numerous advanced blood disorders. It has also spawned the development of other lifesaving medical advances, including today’s burgeoning cellular immunotherapies.
Storb and the other members of that transplant team were founding members of Fred Hutch, which celebrates its 40th anniversary this year. He’s now of an age at which most others would be long-retired. But if you ask him, he still has far too much to do in the lab.
In fact, he and his collaborators recently received two five-year research grants from the National Institutes of Health, totaling $22.7 million, to continue improving transplantation. Once focused on getting desperately ill patients merely to survive, research by Storb today aims to decrease the toxicity and harmful side effects of transplantation to improve the quality of life of patients who receive the therapy he helped to pioneer years ago.
’Never loses touch of patient care’
Two-and-a-half months of every year, Storb cares for transplant patients at University of Washington Medical Center and Fred Hutch’s patient-care arm, Seattle Cancer Care Alliance. It is there, in the clinic, that his commitment to grappling with failures in his research means that he must look eye to eye with those for whom transplantation isn’t yet the perfect cure he is trying to achieve.
“He feels like he failed them,” said Dr. Beverly Torok-Storb, a transplantation biologist who has been a colleague of Storb’s on the Fred Hutch faculty since 1980 and his wife since 1975. It is his somber demeanor when he comes home at the end of the day that gives him away, she said.
Storb thinks about those patients constantly when he completes his clinical service for the year and comes back to the lab, he and colleagues said. He’s consumed by thinking about what he might do to make the therapy better for others in the future.
“He’s hopeful that we will make a difference,” Torok-Storb said. “And he has made a difference.”
Joanne Quinn has seen the difference that Storb makes in patients’ lives firsthand. A longtime Fred Hutch/SCCA nurse, Quinn worked beside Storb on his transplant service this year. Patients react positively to his scientific authority, she said, but also to his infectious optimism and his gentleness.
Laura Landro did. A journalist, Landro’s in-depth research into her leukemia led her from the East Coast to Fred Hutch for a transplant under Storb’s care in 1991. She was immediately taken by his enthusiasm for his work and his open, understanding demeanor.
He has empathy for his patients, she said, and it shows not only in the clinic but also in his work in the lab.
“He never loses touch of patient care while he’s doing the research that’s going to extend their lives,” Landro said during a call from her office in New York.
Tinkering with mistakes
On his previous clinical rotation in July 2015, Storb cared for 53 transplant patients. At one time, these patients would have all been under 50 years old, without any additional medical complications: Grueling pre-transplant preparative regimens of radiation and chemotherapy meant that only strong, young patients had a reasonable chance of withstanding the procedure.
But of Storb’s 53 patients this year, more than half of them were over 60 years old. The oldest was 77. The transplant team even discussed a transplant for an 81-year-old.
The fact that giving transplants of blood stem cells to older patients is now de rigueur is a testament to Storb’s approach to science, with the love of tinkering he developed as a boy in his basement.
When unusually low doses of radiation were delivered by mistake during the Storb Lab’s preclinical transplantation research in the 1990s, Storb took the time to examine the results rather than throw them out as anomalies, said Dr. Brenda Sandmaier, a transplantation physician-scientist at Fred Hutch and UW and a former trainee, and now a faculty colleague of Storb’s.
“Most people would say, ‘Oh, that was a ruined experiment; let’s go back and do what we intended,’” said Sandmaier, who was collaborating with Storb on this research at the time. “But instead, he took this as an opportunity to investigate the phenomena … He tinkered with the regimen.”
This mistake was actually a breakthrough, the genesis of the procedure known today as a non-myeloablative transplant, or mini-transplant, a gentler therapy incorporating lower amounts of pre-transplant radiation. Because it is easier on the body, mini-transplant has extended the benefits of this lifesaving procedure to patients whose advanced age or medical complications once made them ineligible to receive it. Because mini-transplants are outpatient procedures, patients don’t require lengthy hospital stays; in fact, they can live at home.
Quinn, the transplant nurse, sees the impact of Storb’s research breakthrough every day in the clinic.
“On this team there are many elderly patients who have benefited from this nonablative transplant — they never would have met the criteria long ago. That’s because of him,” Quinn said. “Despite the advanced age of many of our patients on this team (during Storb’s service this year), if they’ve had some rocky spells, they’ve recovered.”
Long-envisioned goals are in sight
Even with such astounding progress, Storb is still doggedly focused on making transplantation better. Now, the solutions for problems he’s been facing for years are in sight, he thinks, and his goal is to solve them before he takes his first step back from the role he’s held at the Hutch for decades.
Toward this aim, he’ll be aided by the support of the massive research grants he was awarded this year.
A year ago, a team co-led by Storb and Sandmaier received $9.8 million from the National Cancer Institute to study ways to reduce post-transplant risks. Storb’s project focuses on preventing the acute form of graft-vs.-host disease — a common and sometimes deadly complication in which transplanted immune cells attack their new host’s body — and treating the chronic form of the condition. He will be carrying out preclinical testing of tailor-made, targeted drugs designed to shut down harmful immune reactions before they get out of hand.
This research is a continuation of years of work for Storb on this complication, which still besets a large fraction of transplant recipients, even if it is no longer as fatal as it once was. In the 1980s, Storb and collaborators developed what is now the standard-of-care treatment for GVHD, a cocktail of two immunosuppressive drugs that tamp down the transplanted immune cells’ attacks. But the disease is still “the bane of our existence,” Storb said, leading to long durations of treatment and the risk of disability, and worse, for patients.
He is hopeful that his new approach will make the difference in the next few years.
“I’m still believing that we should be able to crack this graft-vs.-host disease problem. That’s what I’d like to accomplish,” Storb said.
He also would like to develop safer treatments to prepare patients for transplant, he added.
In early July, a research team led by Storb and Dr. Hans-Peter Kiem received $12.9 million to improve transplantation-based therapies for noncancerous diseases of the immune system and red blood cells.
Through this project, Storb will carry out clinical tests of a targeted, safer form of pretransplant radiation. This approach couples a molecule called a monoclonal antibody to a powerful radioactive isotope, designed to seek out only the cells of the patient’s body that must be destroyed for the subsequent transplant to succeed. In this way, patients will be spared full-body blasts of radiation that can damage tissues throughout their body and increase their risk of developing cancer later in life.
The question he wants to answer in the next few years is: Can he make patients’ lives not only possible, but healthy and long?
A growing impact
Storb loses track of most of the patients whose lives he’s saved. They get better, they go back home, they get back into living their lives. They move on. It’s a good thing, he says.
But he loves seeing them again, all the same.
There was the man who received in 1971 the first-ever successful transplant for the blood disorder called aplastic anemia, who showed up at Storb’s office one day several years ago just to say hello. There was the German sexagenarian who let him know that she took up hang-gliding after her transplant. And there are all of the transplant recipients from the past three-plus decades who come back to the Hutch every five years for the Bone Marrow Transplant Reunion.
The impact of Storb’s career includes not only the growing list of former patients, but the next generation of researchers who are carrying his innovations forward. Storb has mentored more than 150 early-career scientists over the past 40 years, who have gone on to faculty positions around the world, from Canada to Australia, from Switzerland to Japan.
This June, Storb celebrated his 80th birthday with his wife and friends. The next day, he rowed in an eight-mile race in the Puget Sound as part of a four-man team. He’s always been an athlete but became a dedicated rower after buying a waterfront home in Seattle four decades ago. He’s now hooked his son, Adrian, 37, on the sport, and the two of them often row together.
It’s the rhythm of the stroke, says Storb: drive, recovery; drive, recovery; drive, recovery. If you’re alone, he says, you can get so entranced you can go for miles and miles without realizing it. You see dolphins leaping, seagulls alighting on the water, boats going by. Your whole body is working in unison to propel you forward through the water while your conscious mind slows down.
Storb’s father, Werner, worked continuously until age 77, when he was struck and killed in a crosswalk on his way to a Sunday house call. Like him, Storb can’t imagine slowing down.
When he hits his 85th birthday, Storb thinks he’ll continue his science but hand leadership of his projects over to his colleagues. It’ll give him an opportunity to summit Mount Rainier — again — and dedicate more time to rowing and designing new rowing shells for the California-based company that he, Torok-Storb and friends bought in 2012.
But until then, he has work he needs to do.
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Susan Keown is a staff writer at Fred Hutchinson Cancer Research Center. Before joining Fred Hutch in 2014, Susan wrote about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at skeown@fredhutch.org or follow her on Twitter at @sejkeown.
