The legacy of a pioneering transplant immunologist

Hutch News

The legacy of a pioneering transplant immunologist

‘So much to be learned’: Dr. John Hansen reflects on the lives he’s saved and the answers still to come

July 11, 2018
current headshot of Dr. John Hansen in his office with books in the background

Dr. John Hansen has made major contributions to the development of bone marrow transplantation, which has now offered the chance for a cure to over a million people worldwide.

Photo by Robert Hood / Fred Hutch

A man in Japan rubs the inside of his cheek with a swab to collect some of his cells. He’s sending them off to enter a database of people willing to donate their blood stem cells to strangers in desperate need of a bone marrow transplant.

At the same time, a doctor in Germany logs in to a web portal. She carefully enters information about one of her patients, a man with advanced leukemia. Then, she hits search. A few seconds later, the system lets her know about a thousand people around the world who could be suitable matches for her patient. Will one of them be the bone marrow donor who saves his life?

On the other side of the planet, a cloud of liquid nitrogen vapor spills from a silver tank in Seattle. A rubber-gauntleted technician draws out a frost-encrusted metal rack, full of vials of decades-old blood cells suspended at 192 degrees below zero. A scientist will be applying new genomic technologies to analyze these old samples and crack open clues to better cancer therapies.

And 200 feet away from her — across a road, through some doors and up a set of stairs into a quiet office overlooking a tree-filled courtyard — sits a man who played an outsized role in making all these things possible. 

In his puffy Patagonia vest and jeans, Dr. John Hansen looks every inch the Seattleite he has been since he arrived in the city in 1977 to work at Fred Hutchinson Cancer Research Center. At that time, a small team at the nascent institution was working to develop a radical, controversial therapy called bone marrow transplantation under the leadership of Dr. E. Donnall Thomas.

Today, a Nobel Prize to Thomas for the development of the procedure hangs proudly on the Hutch campus, and transplant is considered standard of care for patients with certain advanced blood cancers and immune deficiencies. In a bone marrow transplant, a patient’s diseased blood and immune system is suppressed or destroyed and replaced with a healthy one from a donor. (View our step-by-step visual guide to bone marrow transplantation.)

A career of contributions

Hansen is a quiet man. With patients, he listens more than he talks. Colleagues who have worked with him for decades can’t remember ever hearing him raise his voice in anger, and they remark on how even Hansen’s most critical scientific reviews leave the person on the receiving end feeling positive.

Steady and systematic in his science, Hansen is nevertheless capable of great leaps of creativity, colleagues say — qualities that undoubtedly helped him advance research in the face of the many great challenges of early transplant science. And, as someone who naturally shies from the spotlight, Hansen is reluctant to bring attention to his achievements.  

They are many.

A middle-aged Hansen and a young man smile at each other through a plastic barrier.

Hansen with a transplant patient, who is in protective isolation in a special germ-free room.

Fred Hutch archives

Hansen, now 75, has made fundamental contributions to the field’s understanding of how genetic variation in the immune system contributes to transplant success or failure. He has helped define the rules for finding suitable donors for each transplant patient, and he played a key part in the establishment of registries of potential bone marrow donors, who now number in the tens of millions worldwide. He started collections of biological samples and data that have become crucial resources for countless researchers worldwide. And he has held local, national and international leadership positions in his field.

Last year, Hansen was diagnosed with the disease he has dedicated his career to overcoming. He will transition to emeritus status at the end of this month as he continues undergoing care for his malignancy, a pancreatic cancer. As emeritus faculty, he will be able to continue working at his own pace to discover answers to the types of questions that have driven him for more than four decades. And he’ll place the last bricks in a scientific foundation that, his peers say, will give rise to many more lifesaving discoveries by others to come.

“Most of us are not going to be Alexander the Greats who get into the history book,” said Dr. Paul Martin, Hansen’s first laboratory trainee in Seattle and now one of his collaborators on the Hutch faculty. “But at least over the immediate future, it’s easy to see that John, in the work that he’s done historically and continuing to do in this coda, really has made a profound impact on the field. And it continues to be true.”

From the heart to the immune system

Hansen found his way to bone marrow transplantation — and Fred Hutch — via heart surgery.

In medical school, Hansen worked in the lab of heart-transplant pioneer Dr. Norman Shumway. Shumway’s team was facing a big challenge: immunological rejection of the transplanted heart. So, with a cardiac surgery fellowship at Stanford waiting for him, Hansen went off to London to learn immunology in pursuit of better heart transplants. But there was so much more to be learned. So he went off to Minneapolis to learn some more immunology.

It just so happened that his immunology mentor at the University of Minnesota was Dr. Robert Good, who had performed the first successful human bone marrow transplant in the world — on a little boy born with a severely compromised immune system — just a few years before.

Learning about bone marrow transplant was a revelation for young Hansen, who was increasingly aware that his calling lie with the immune system, not the heart. He remembers lying awake at night obsessed with thinking about how the knowledge he was gaining about immunology could be translated into new ways to save lives.

“Then I realized, holy cow … that was the answer for sure. The answer was transplantation,” Hansen recalled. “Not just heart or kidney transplantation, but replacing an immune system, or treating leukemia.”

He never returned to Stanford for that cardiac fellowship.

Tissue-typing opens a door to better matches — and mismatches

Photo of three men and a woman in formalwear, smiling for camera

Hansen with Thomas, Thomas' wife and research partner Dottie Thomas, and then-Hutch President and Director Dr. Robert W. Day at the 1990 Nobel Prize reception.

Fred Hutch file

Several years later, the Hutch transplant team invited Hansen to lead their big new tissue-typing lab. He has headed the clinical typing lab for the Fred Hutch transplant program ever since.

Tissue type, or HLA, refers to an immunological system for recognizing self versus foreign. Discrepancies between HLA genes in a patient’s cells and those in transplanted cells can cause transplants to fail. In the Seattle HLA lab, Hansen and his group developed tests to help the transplant team know whether a particular patient had a well-matched marrow donor. They continuously incorporated new technologies to improve their methods, which were widely adopted and built on by labs around the country.

He and his colleagues also meticulously gathered data on how donor matching mapped to patients’ results after transplant, which helped inform the next rounds of research to improve transplantation.  Hansen’s clinical studies helped extend the pool of patients who could find suitable matches. In particular, Hansen led clinical trials that showed patients could still have good outcomes from transplant from a family member who was not a perfect HLA match.

“He really helped establish the rules in the early '80s for how far you could go in mismatch and still be successful,” Martin said. Today, a growing number of transplants are of half-matched cells from a family member.

A fortuitous meeting kicks off a movement toward unrelated-donor transplant

But, thanks in great part to Hansen, a patient’s donor pool now extends far outside their family.

During Hansen’s first years at the Hutch, the transplant team could only provide transplants to patients who had HLA-matched sibling donors. But only about one out of every three patients who might benefit from transplant had a matched sibling. And the demographic trends were clear: Families were having fewer kids, which made the chance of sibling matches even lower in the future. This grave and growing problem gnawed at Hansen.

“The obvious solution was unrelated donor transplant. The big problem was, we didn’t know enough about the HLA system,” Hansen said.

As he and his team slowly filled in those missing pieces of the HLA puzzle, Hansen met the Graves family, and transplant medicine would never be the same.

Dr. Robert Graves had learned of Hansen’s work in HLA typing for bone marrow transplant, and he traveled all the way from Colorado to speak with him about the terrible situation the family had found itself in. The family’s young daughter, Laura, had relapsed leukemia. Although she had three siblings, none of them were good matches. But Laura had a common HLA type, Graves knew. Would it be possible for her to receive a transplant from a donor who was not her sibling?

That was exactly the question that Hansen and colleagues had been asking themselves. Laura’s common tissue type offered an opportunity. Looking into his files of research blood donors, Hansen found, to his surprise, not one but four potential matches for Laura. One of those, a 26-year-old lab tech, agreed to donate marrow. So Hansen and his Hutch colleagues gave the 10-year-old one of the world’s first successful unrelated-donor bone marrow transplants on Sept. 4, 1979.

Laura recovered well, but her reprieve did not last. Tragically, her cancer returned less than two years later and, this time, there was no more that could be done to save her. And yet the hopeful idea that came to life through her transplant had already taken root. What if other patients who need a transplant could find well-matched unrelated donors? Given the diversity of the human race and, thus, in HLA type, it would require a staggering number of volunteer donors to locate good matches for most patients. But what if it could be done?

The Graves family spearheaded a movement of other patient families, Hansen and other physicians, and, critically, key advocates at high levels of government, which resulted in a landmark 1986 federal law establishing the first-of-its-kind National Marrow Donor Program. Hansen teamed up with two colleagues at blood banks in Minnesota and San Francisco (Drs. Jeffrey McCullough and Herbert Perkins) to plan and set up the registry.

Could you save a life?

At bethematch.org, you can learn about registering as a potential donor of bone marrow or other blood stem cells, or learn how to donate your newborn’s umbilical cord blood.

If you live outside the U.S., find out if there’s a registry in your country.

In December 1987, the first transplant through the registry came to pass. The Wisconsin National Guard was called in to clear the snowbound Milwaukee airport so a small private plane could take off and ferry those precious cells from a Wisconsin donor to Seattle, where the transplant team waited to put them in a 6-year-old girl with leukemia.

“Every patient that I’ve known, every patient I’ve helped — and by now that’s a lot of patients — every one of them is a precious experience, a real sense of accomplishment,” said Hansen, who served for 16 years on the registry’s board of directors. “But getting the national registry started was also like that. And now, oh my gosh, it’s huge.”

Indeed. More than 4,000 transplants of blood stem cells from unrelated donors occur each year in the U.S. alone — twice as many as transplants of cells from blood relatives. The U.S. registry, now called Be The Match, reports having nearly 12.5 million potential donors on file. Millions more are recorded in partner registries worldwide that were built after the U.S. model.

Hansen’s research on tissue typing and donor matching facilitated the identification of suitable unrelated donors through the registry. At the same time, as the registry enabled more and more transplants from unrelated donors, there was a growing body of data on outcomes from unrelated-donor transplants, which then has helped further refine matching techniques.

Meanwhile, a growing list of advances by other investigators has made transplantation a therapeutic option for more and more patients in need — such as the use of cells from umbilical cord blood, which don’t require as-perfect matching as a transplant of adult-donor cells, and the development of less-toxic procedures for older and sicker patients.

Today, every patient who could benefit from transplant can find a donor.

With critical research resources, ‘mysteries become uncovered’

black and white photo in a laboratory. Hansen and another man are in the foreground near a microscope. Another man sits in the rear at a fume hood and a woman in the background appears to be getting supplies out of a box.

Hansen in the laboratory with team members Sandra Orcutt, Patrick Beatty and Jim Jenkins, c. 1989 or 1990.

Fred Hutch file

Hansen’s establishment of critical scientific resources has helped ensure that these advances keep coming.

As he worked to set up the National Marrow Donor Program, Hansen was instrumental in establishing the program’s repository of paired samples from transplant patients and donors. The resource is now is part of an international repository that contains samples and data from nearly 50,000 donor–recipient pairs.

Hansen had “remarkable” foresight in anticipating the value that future researchers would find in samples and data related to immunology and bone marrow transplant, said his former mentee and now colleague Dr. Effie Wang Petersdorf.

“You can’t even begin to quantify how important that resource is,” said Petersdorf, an HLA expert whose own research has relied on the repository. “Almost every major study that has sought to answer a question related to the importance of a gene or polymorphism has leveraged that resource.”

The sheer size of this resource is its power, said Fred Hutch Executive Vice President and Deputy Director Dr. Fred Appelbaum. “Once you have thousands to hundreds of thousands of samples, you find things that you can’t find in small populations. Mysteries become uncovered,” he explained.

That isn’t the only important research asset Hansen has set up. His laboratory became Fred Hutch’s Research Cell Bank, a shared repository of cells and genome sequences. For example, the bank holds a cellular reference library created by an international working group once headed by Hansen, which catalogs the diversity of human HLA genes and other important immunologic genetic variants. It is relied upon by academic investigators and biotech companies worldwide for quality control in immunological typing and is one of the most well-studied resources of its kind, Petersdorf said.

Unanswered questions and ‘the greatest payload’ for medical science

Despite all the questions his research has helped to answer over the years, Hansen’s eyes still focus on the many still unsolved. One of these is how can transplanted immune cells be stopped from attacking the patient’s healthy cells (a complication called graft-vs.-host disease)?

“If you were able to fully understand that process, that mechanism, it would be almost certainly relevant to all the autoimmune diseases, like rheumatoid arthritis, lupus, multiple sclerosis,” Hansen said. “So the secrets of the immune system, I think, are still the biggest challenge for 21st-century medicine. And, perhaps … may be harboring the greatest payload for advancement of the treatment of disease.”

Bone marrow transplantation provided the first definitive and reproducible evidence that the immune system could be harnessed to cure cancer. Today, a wide range of immune-harnessing therapies, broadly called immunotherapies, are transforming the treatment of many different cancers.

Hansen’s discoveries about the immune system are helping to pave the way in this revolution, in transplantation and beyond, Appelbaum said.

“Every piece of the puzzle that John has helped to unravel about all the parts of the immune system that contribute to responses in the setting of transplantation will continue to have a really important relevance to what happens going forward,” said Appelbaum, who has been an occasional collaborator of Hansen’s for decades.

In partnership with his former trainee Martin, Hansen is working on a research project, a decade in the making, that they hope will provide a springboard to that future.

In this study, Hansen and Martin and their teammates are mapping out how tiny variants sprinkled throughout the genomes of 4,500 patients and their donors affect a variety of transplant outcomes, ranging from graft-vs.-host disease to infection to death. Unlike the large effects that individual HLA genes have on transplant outcomes, each of these variants has only a miniscule effect on its own. Patterns of how they all play together to affect a patient’s health only become apparent within big data sets like this one.

The pair hope that the discoveries they make through this “capstone project,” as Martin describes it, help improve transplant matching, reveal targets at which to aim new immune-modulating therapies for cancers and other diseases, and inform new science by the next generations of researchers.

Outside Hansen’s window, the courtyard is paved with bricks and slates that are engraved with messages from supporters, families and patients treated by Hansen and his Hutch colleagues. Some of these engravings commemorate joyous milestones of survival. Others are in memory of those who did not make it.

The light filters gently through the green leaves outside and comes to rest where Hansen sits next to a shelf holding a lifetime of awards.

“There is still,” he said, “so much to be learned.”

Has Hansen's work impacted your life or that of a loved one? Tell us on Facebook.

Susan Keown, a staff writer at Fred Hutchinson Cancer Research Center, has written 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 on Twitter @sejkeown.

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