Nothing is more invigorating than a hypothesis.
Primo Levi, Flaw of Form
To transplant or not to transplant? That, with apologies to Shakespeare, is the question for many blood cancer patients.
Whether they plan on getting one or not, patients and caregivers should have some general knowledge about bone marrow transplantation (BMT). Although myeloma is a very small part of the story, BMT’s history informs virtually every treatment.
Physicians routinely determine if newly diagnosed myeloma patients are transplant-eligible or -ineligible. And that’s still a long way from actually getting one if eligible. Indeed, a minority of myeloma patients have one. The choice charts the treatment roadmap, one which very likely will have unexpected detours along the way.
BMT’s underlying concept is as old as medicine itself. Hippocrates separated medicine from the realm of religion more than 2,400 years ago, positing diseases had earthly, not divine causes. The body had the power to heal itself and could be assisted by using herbs and other methods to treat diseases, thus beginning a seemingly eternal medical crusade in search of the Holy Grail of curing diseases. By the late 19th century, “heal thyself” was taking shape as a new field of science.
Immunology is a concept of which all cancer patients should have a minimal understanding. One way to learn is to search the internet, which can be especially daunting for a variety of reasons. Most do not have the education or experience to properly interpret such complex information. Scientific papers aren’t the best reading for lay persons, especially if no overall narrative to explain and put things into context exists.
Fred Appelbaum, Executive Vice President of the Fred Hutch Cancer Center in Seattle, does just that in Living Medicine: Don Thomas, Marrow Transplantation, and Cell Therapy Revolution. Don’t let the subtitle fool you into thinking this is a heavy academic tome.
Appelbaum tells this story in regular language. While academic jargon is unavoidable at times, his descriptions and explanations have the feel of a physician in an examination room taking needed time to explain a diagnosis, looking his patients in the eye, informing them that their lives will never be the same again. Something virtually every cancer patient and caregiver understands viscerally.
E. Donnal “Don” Thomas’s pioneering of BMT over almost four decades was built on a singular, focused vision: using bone marrow, the “engine” that creates immunity, from a healthy donor and transplanting it into another whose marrow has been damaged. Recognized for the impact of his ideas, Thomas received the 1990 Nobel Prize in Medicine. Appelbaum explains the history leading up to the award and how its legacy shapes today.
Born in 1920, Thomas was the only child of a rural Texas physician who often joined his father when making house calls in a horse-drawn wagon. Although self-described as “not an outstanding student,” he went from a one-room schoolhouse in rural Texas to earn his MD in 1946. Following graduation, he worked with Sidney Farber, whose trailblazing use of chemotherapies in childhood leukemia created one of the foundations of modern cancer research and treatment. (Farber’s story is told exceptionally well in Siddhartha Mukherjee’sThe Emperor of All Maladies, the first of a “trilogy” that I’ll discuss later this summer.) The relationship sealed Thomas’ focus on bone marrow and leukemia.
A philosophical difference between the two led Thomas to Cooperstown, New York in 1955, which seemed a strange place to do cancer research. But, as he described in his Nobel acceptance speech decades later, Cooperstown gave him freedom “to work on marrow transplantation in human patients and in the dog.” Animal model research was still relatively new then, dogs were considered to be the best animal model prior to human testing. (The idea of using animal models to develop and test drugs for human use, widely prevalent today, was first done by E.M.K. Geiling and Frances Oldham Kelsey in Chicago.)
While colleagues around the nation and world saw the potential in what Thomas was trying to do in BMT – a young Robert Kyle was sent by William Damashek to Cooperstown to observe and learn Thomas’ methods – he had little tangible success in the form of surviving patients. Nevertheless, colleagues invited him to speak, to share his theories and lab results.
Although Thomas didn’t have a lot of positive results to report. The history of vaccines, also a form of immunotherapy, served as a precedent of sorts. Scientists around the world recognized, to put a reverse spin on Gertrude Stein’s aphorism about Oakland, that there was definitely some “there there.”
In retrospect, Thomas’ early attempts seemed almost primitive, literally taking bone marrow from one donor and putting in another. The goal was engraftment; the donated marrow would “take over” the functions damaged marrow couldn’t produce. The consequences, however, could be horrid and more than often, fatal.
Transplanting bone marrow from one person to another, known as allogeneic transplant, proved to be “very difficult.” The donated marrow became an aggressive, incompatible “invader” of sorts, causing graft-versus-host-disease (GvHD), a common side effect in which donated marrow would attack not only disease, but healthy tissues and organs, potentially with fatal consequences.
Invited to speak in Seattle, Thomas “acknowledged his frustration that he had yet to show that marrow transplantation could cure anyone,” the two biggest hurdles being the inability of donated marrow to engraft and GvHD. Following the lecture, he was approached by physician claiming, “We have the ideal patient!” A patient of his was young girl, Nancy Lowry, who had “Aplastic anemia, first described by Paul Ehrlich in 1888…a terrifying and mysterious disease in which the marrow suddenly stopped working.” The possible good news was that she had an identical twin sister.
“With an identical twin,” they reasoned, “there should be no risk of graft rejection or (GvHD), and unlike Thomas’s leukemic cases, there was no malignant disease to eradicate.” Nancy’s sister, Barbara was “struck forty-four times with an 18-gauge needle, each time removing a teaspoon or two of marrow” from her hip and shin bones.
After initial fears of failure, within two weeks Nancy experienced engraftment. White cells began to proliferate in her marrow, her health improved dramatically. “Now more than sixty years since the transplant, Nancy and her donor, Barbara, remain alive, well, and happily retired.”
Identical twin transplant proved to be the first successful immunotherapy and still remains among the most effective blood cancer treatments, especially in myeloma. The first patient I accompanied to a congressional visit to advocate for more research funding in 1998 was an identical twin who had a transplant. She is alive today.
Unfortunately, very few who have the misfortune of being diagnosed with a cancer like myeloma do not have the fortune of being an identical twin with a potential healthy donor. They would be outliers for quite some time to come. The hurdle of transplantation from non-identical donors remained a problem for years to come. In myeloma, allogeneic transplantation remains limited, controversial, and most physicians won’t even consider it.
Before understanding why, it’s important to go back to the beginning of the history of immunology, which had little to do with cancer, before considering the present and a future when cancer treatment without immunology is unimaginable.
In 1882, a Ukrainian-born zoologist working in Italian lab, Élie (also known as Ilya) Metchnikoff, was studying starfish larvae. After piercing them with thorns, he observed inflammation in the tissue surrounding them, leading him to hypothesize something in the larvae must have been triggered by the injury. A year later, at the suggestion of collaborating colleague in Vienna, called them phagocytes – white blood cells protecting and repairing damage. Components making up these white cells, monocytes, macrophages – also known as dendritic cells, and neutrophils – together created the innate immune system.
Building on Metchnikoff’s discoveries, German scientist Paul Ehrlich – who had identified aplastic anemia – was studying possible uses of dyes being developing by German industry for medical utility, which might be seemingly trivial from today’s perspective, but was on the cutting edge of science then. Ehrlich found some dyes had specific affinity – an attraction much like the one Greg Mundy saw with bisphosphonates and calcium in the 1990s – for individual components of blood. Each could be identified by a specific dye under the microscope, making it possible to determine the amounts of each – a forerunner of today’s FISH tests in myeloma.
Ehrlich identified “four lineages…to red blood cells for carrying oxygen, platelets for assisting in blood clotting, and two forms of white blood cells (myeloid and lymphoid), both contributors to our immune defences…Myeloid cells largely work by engulfing (phagocytosing) foreign invaders, while lymphoid cells produce antibodies and kill unwanted cells directly.” He was on his way to becoming “the father of immunology” whose legend produced a rarity in the scientific world, a superstar would later be portrayed by Edward G. Robinson in a 1940 film, Dr. Ehrlich’s Magic Bullet.
Metchnikoff and Ehrlich shared the 1908 Nobel Prize in Medicine “in recognition of their work on immunity.” As knowledge of the mechanics of immunity spread in labs around the world, it was one of the most shocking and tragic ending of World War II that jolted medical experts and transformed cancer treatment: the dropping of the atomic bombs on Hiroshima and Nagasaki.
“When the (Hiroshima) bomb exploded, it unleashed a spray of radiation traveling at the speed of light, penetrating every body in its path, oxidizing cell membranes, damaging proteins, and mutating DNA along the way, silently, instantly.” In the United States, the term “atomic bomb disease” became common.
Most who initially survived the blasts had severe physical symptoms including nausea, diarrhea, and hair loss, many of them died excruciating deaths in weeks and months after the bombings. Autopsies revealed radiation had basically killed their white cells, their immune systems were wiped out by the intense radiation.
Four years after the war, a scientist in Chicago who was a part of the bomb’s development, Peter Jacobson – who, coincidentally was born in a small town in North Dakota that no longer exists, about 140 miles south of Robert Kyle’s birthplace – received a grant to learn more about radiation exposure. His first experiment was to subject 1,000 mice to similar amounts of radiation to that experienced in Japan. All died between one-to-two weeks later.
He surgically removed the spleens of some mice, put them on the outside of the mice, surrounding them with lead, and exposed them to the same radiation before putting them back in the mice. These mice survived. Subsequent variations of this had the same effect. Although he did not know it and decided to go in a different research direction in later years, Appelbaum cites his findings as “pivotal to the field of marrow transplantation.”
While Thomas was in Cooperstown, two researchers in Toronto, James Till and Ernest McCulloch, studied how blood cells regenerate after radiation exposure. In short, they determined there were many more parts to bone marrow than initially thought. And the key elements they identified were stem cells, which would, decades later, lead to the development of autologous stem cell transplantation (ASCT). Which, in turn, would become the dominant type of BMT in myeloma treatment.
Stem cells in general are the seeds that create all parts of the human body. Hematopoetic stem cells create the various elements of blood, first identified by Metchnikoff. Some have a specific purpose, others are pluripotent, meaning it can eventually develop into a variety of cells and tissue. Each are are differentiated, meaning “Once a cell is committed, there’s no turning back.” Their output over an average lifetime is both impressive and humbling, however the aging process often causes “stem cells to run out of steam.” It’s easy to understand why.
“Estimates are that an adult human has anywhere from 3,000 to 10,000 hematopoeitic stem cells…red cells live for a few months…platelets for a week or two, and…white cells, depending on their type, only a day or two.” [Emphasis added.] Healthy stem cells directed the creation of essential elements need to make the body function as advertised.
Till and McCullough built on Ehrlich’s ideas from more than half a century earlier. He identified the second type of immunity, it was adaptive. Innate immunity, when healthy, runs on its own, it is self-generating and -protecting. Adaptive immunity requires B cell and T cells of blood. When exposed to foreign invaders, they create antibodies as aggressive defenders. We’ll come back to this many times in future articles.
By 1965, Thomas accepted an offer to take his work to Seattle’s Public Health Hospital to make Seattle his permanent home. Although working conditions were relatively primitive, he was given space, a few in-patient beds, and more staff. But by the early 1970, Public Health Hospitals began closing, a potential disaster for Thomas. Thankfully for him, President Nixon had just signed War on Cancer legislation that increased the number of comprehensive cancer centers (CCCs).
Washington Senator Warren Magnuson successfully lobbied to designate Seattle’s Fred Hutchinson Cancer Center (Fred Hutch), but “comprehensive” would have a different meaning once Thomas moved his entire lab to Fred Hutch in 1975. Unlike those centers, Fred Hutch would focus almost exclusively on BMT research and treatment. Seattle would soon become a Mecca for patients throughout the world who needed transplants.
Growing success and acceptance of transplant therapy spurred medical institutions throughout the United States and Europe to invest billions in facilities, staff, and education in the early 1980s. Seemingly all of them sent physicians to Seattle to train under Thomas’s staff in BMT-related fields, including Ralph Naumann from Germany.
BMT was still a relatively risky procedure with high mortality rates when Thomas accepted the 1990 Nobel Prize, but what it could report in patient survival was spectacular and unprecedented. The “there there” was becoming obvious, observable, and repeatable. It was not quick but progressing deliberately. Family members who lost loved ones overwhelmingly were aware of the risks, grateful for the effort, especially Thomas’s staff of physicians, nurses, and other health professionals, and became life-long champions.
Unlike most clinics, Thomas hired staff to annually stay in touch and track their patients preferably for life. They primarily conducted allogeneic procedures for leukemia and lymphoma patients, refining the procedure to minimize side effects and maximize quality of life. Problems, however, would continue and Appelbaum does not shy away from them.
“Marrow transplantation ranks among the ten most expensive medical procedures routinely performed in the United States today.” The costs have less to do with the procedure itself, but everything it requires – a month or more in acute hospital care, medications, blood for transfusions, lab fees, and imaging. That adds up: “there about 15,000 autologous and 10,000 allogeneic transplants performed in the United States every year.” The vast majority of the former are for myeloma.
Long-term childhood leukemia survival rates went from around five percent in the 1950s to more than 95 percent today. While the majority of adult patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) choosing transplant have related donors, some clinics report as many of fifty percent of their patients get marrow from unrelated donors.
Thomas and his team were the inspiration of Be the Match, a bone marrow data bank. People throughout the world voluntarily commit to donate their marrow to anonymous patients if it is a promising match. More than forty million people registered worldwide. In 1990, the registry crossed one million.
Appelbaum’s insights link BMT potential transformative therapies such as CAR T, bispecific antibodies, and vaccines are transforming myeloma care. The goal of these therapies, much like BMT, is to make a patient’s bone marrow and immune system to function as advertised.
For the past two decades, advances in myeloma treatments entering clinical practice, raising hope that ASCT/BMT might soon become obsolete. But that day is not today. In the United States, myeloma patients account for about 10,000 ASCT procedures annually. This fact alone should make this book relevant to the myeloma community.
The ideas behind cancer therapy often come from the strangest places, especially for myeloma. It is notable that two of the most used therapies have their roots in war. Chemotherapy’s is in the mustard gas used in trenches of World War I and the tragic World War II disaster of the Bari, Italy bombing of ships containing it. BMT’s is in the tragedy of World War II’s ending. A third, bisphosphonates, have origins in solving the problem of calcium accumulating in sewer pipes.
Appelbaum’s at times charming account of Thomas’s work and influence covers all the essential bases for lay and professional readers to put these seemingly random facts and events into a readable context, a rarity in medical writing. His chronicle of the implications of Thomas’s stubbornly trod intellectual footprints, where the various practical paths led to develop new therapies will help to better understand the big picture of the global effort to control and eradicate cancer.
Strongly consider putting it on your summer reading list.
Apologies for missing the Wednesday-Sunday cycle of posts yesterday. I’ve been a bit under the weather.
In the next article, I’ll introduce the ground-breaking iconoclast in myeloma who is an obvious choice for the second spot on myeloma’s Mount Rushmore, along with Robert Kyle.
Living Medicine: Don Thomas, Marrow Transplantation, and the Cell Therapy Revolution, by Fred Appelbaum, Mayo Clinic Press, 305 pp., $27.99 (Hardcover)
Thank you Greg. I findyour essays fascinating and well written. I thought I knew quite a lot about myeloma, having lived with it thanks to 2 stem cell transplants, for just over 17 years. Have you read The Immortal Life of Henrietta Lacks by Rebecca Skloot? It’s a fascinating account of the life of the woman whose cell lines, “hela cells” are still in use today. Her cells were used to develop FISH testing for myeloma.