Dr. Arnold Caplan, “Arnie” to his thousands of colleagues and friends around the world, left us on January 10, 2024.
Dr. Caplan was professor of Biology and director of the Skeletal Research Center at Case Western Reserve University. He also was the lifetime achievement award winner from the Tissue Engineering and Regenerative Medicine International Society.
Titles, however, don’t describe Arnold Caplan’s life work—which became a foundational body of knowledge in the musculoskeletal field—expressed in more than 400 published papers—translated into multiple clinical therapies, brought to life as start-up companies and—above all—carried forward by the scientists he trained, entrepreneurs he inspired, and patients whose pain and disability his insights relieved.
Dr. Caplan’s unifying vision of regenerative medicine lived within an exceptionally creative, warm. and generous mind. His legacy will drive musculoskeletal care for generations to come.
Too Soon
Last October, less than 90 days before he died, Arnie and his wife Bonnie Caplan were visiting their son, Aaron, who said, “Dad, you don’t look so good, you look yellow.” A couple days later, a doctor told Arnie and Bonnie that he had a blockage in one of his liver’s biliary ducts.
The surgery went well. His doctors removed the blockage and inserted a stent to keep the duct open. Arnie recovered well. The yellow pall was gone. But when his doctors got the report back from pathology, they found that Arnie had a metastasizing liver cancer.
A week after Thanksgiving, December 5, Arnie had surgery to remove his cancerous lobe and then, hopefully, with chemo and other treatments, begin the healing process. It didn’t work out that way.
The day before Arnold Caplan had the liver surgery, he had walked for two miles and felt ok.
The surgeons couldn’t remove his lobe because the cancer was more extensive and in more locations than they’d expected. Over the next couple of weeks, doctors tried various strategies to attack the cancer. Nothing worked. Then Arnie said “stop.”
On January 3, 2024, Bonnie, sent the following email to Arnie’s global community of colleagues and friends:
“Here is where we are: Arnold is stable, but he is 100% done with this entire process and does not see a positive outcome to further procedures and he is not willing to endure any further pain, indignity, and overall suffering. He has stated that he wants to take the path of hospice.”
Arnold’s birthday was two days after that email. The response to Bonnie’s email from around the world was, in Bonnie’s words, “overwhelming.”
“People from all over the world responded,” remembers Bonnie, “They passed my email on. The responses began to come, and Arnold loved reading them. He answered some of the emails. But the outpouring from around the world was quite an experience. It was the never-ending response of: ‘I love you, Arnie’.”
Arnold’s friends started to stream into Cleveland for his birthday.
On Friday, January 5, to celebrate Arnold’s 82nd year, more than 50 of his friends and colleagues were in a conference room at hospice.
Throughout Arnie’s stay in the hospital, he was never alone. Bonnie, Aaron, and his daughter Rachel took shifts. A handful of young college students also joined the small group.
It had been five and a half weeks since Arnold entered the hospital. To Bonnie and the family, it felt more like an intense and brutal five months.
January 5, Arnold’s birthday, arrived. He was looking forward to seeing everyone. Remembers Bonnie, “His birthday was on Friday. He was brought to the hospice place, which was quite lovely, actually, on Thursday afternoon. And I had arranged that we would have a gathering. We had a great big cake. It said love. It was pretty, it was cheery.”
“But then that morning, he said to me, ‘I can’t do this’. The idea was to wheel his bed into this big room and then people would talk to him. And I told Arnie, ‘I’ll protect you. If it’s too much, I’ll protect you.’
“So he agreed to go. Around 50 people came, was a great big room. He had what he called a fabulous time.”
“He talked to everybody. He held hands. I didn’t have to protect him. After an hour, it was enough. And he went back to his room.”
Over the entire time, Arnold’s family was with him constantly and had those essential conversations with Arnie, shed rivers of tears, expressed their love and…said goodbye.
On January 10, a Wednesday, with his son Aaron by his side, Arnold Caplan drew his final breath.
The Beginning
Arnold Caplan was born January 5, 1942, and grew up in a tough Chicago neighborhood. His father, David, whose formal education ended at 8th grade, worked a lot of different jobs including, for a while as bagman (the guy who collected the money) for a pool hustler. Arnold’s mother, Lillian, the youngest of 10 children in her own family, graduated from high school and worked for a while as a secretary.
Arnie, David and Lilian’s first-born child, had four sisters.
And he went to college—the Illinois Institute of Technology. Arnie was the first person in his immediate—plus his father’s and mother’s—family to go to college. Arnold Caplan was a kind of miracle kid.
Arnie’s neighborhood was Italian with some Jewish, though not a lot. If somebody approached Arnie and said, “Are you Jewish?” He’d punch the guy. Arnie’s dad taught him how to fight—if there’s one person, you punch him. Two people, you punch them. Three or more, run.
“Nobody had any money,.” remembers Bonnie. “Arnold had saved up, like, $600 bucks to go to the Illinois Institute of Technology. His parents gave him, I think, $7 a week for the bus to Illinois Tech.”
The Illinois Institute of Technology, a private research university was, at the time Arnold enrolled, the largest engineering school in the United States. Among its many distinctions, was a stunning Mies-designed campus (Ludwig Van Mies De Rohe is considered to be one of the fathers of modern architecture).
Its alumni include three Nobel Prize Laureates, two Fulbright Scholarship recipients, one recipient of the National Medal of Technology and, in 1964, a young chemistry major, Arnold Caplan.
Arnold was a smart and curious student. His grades were excellent, he loved research, so he applied to graduate schools and managed to be accepted by Johns Hopkins University.
“Johns Hopkins opened a whole world of diverse students, people from all over the world,” remembers Bonnie.
While Arnie was at Illinois Tech, Bonnie was at Roosevelt University. She had dated a couple of Arnie’s fraternity brothers, which introduced her to Arnie. They stayed in touch after graduation (Bonnie went to graduate school at the University of Illinois and Arnold when to Johns Hopkins).
“At Christmas time 1964, Arnie came back to the city. He called me and said, ‘You want to have coffee?’” remembers Bonnie. “We went out. I had a car. He did not. And I got home at two in the morning. My parents were not pleased.”
They stayed in touch. “We wrote letters. We wrote about values, what we wanted to do, how our lives were,” remembers Bonnie, “Arnie was funny. Interesting. I had dated a lot but Arnie just sort of checked all the boxes.”
On July 4, 1965, they got married. Bonnie moved to Baltimore. With her master’s degree she found a job at a home for unwed mothers and Arnold began his Ph.D. study in Albert Lehninger’s lab at Johns Hopkins Medical School.
Challenging Both Dogma and Lehninger
In a 2020 published interview with Anthony Atala, M.D.[i], the G. Link Professor and founding director of the Wake Forest Institute for Regenerative Medicine a, Arnie recounted the following formative moment in his career:
“I was a graduate student in the laboratory of Albert Lehninger at Johns Hopkins Medical School.”
Lehninger had, in 1948, discovered along with Eugene P. Kennedy that mitochondria are the site of oxidative phosphorylation in eukaryotes, which ushered in the modern study of energy transduction in cellular biology. It was, at the time, the cutting edge of biochemistry.
Arnold Caplan, a researcher in Lehninger’s lab was drafting a manuscript—his first—and had sent it to Professor Lehninger for review. This was 1965.
In the discussion section of the draft, Arnie hypothesized that calcium ions might well be transported into the mitochondrial interstices passing inward from the outside media and eventually passing through the inner membrane and that it had nothing whatsoever to do with the oxidative phosphorylation chain—countering the dogma at the time.
Transporting calcium was, Arnold suggested, an indirect activity, not, as Lehninger taught, a direct connection. “This not only went against the dogma in Lehninger’s laboratory but also was in opposition to his published interpretation,” remembered the Dr. Caplan, “which stated that calcium transport into the interstices of the mitochondria happened through the functioning of the electron transport chain itself.”
Unbeknownst to either Dr. Lehninger or Dr. Caplan at the time, at Glynn Research Laboratories, Bodmin, Cornwall, UK Professor Peter Mitchell was also thinking that the electron transport was an indirect activity. He postulated that there was no electron transport chain, per se, but rather an electrical potential differential between the inside and outside of the inner mitochondrial membrane that was controlled by hydrogen ion transport.
For that insight Mitchell received the Nobel Prize in 1978.
Dr. Lehninger compelled the young Dr. Caplan to edit his discussion section and bring it in line with the lab’s traditional views.
“It not only hurt my pride but also, in the end, was a block that impeded innovative thought and potential progress in that field of study. The other takeaway from this experience is that it will require a huge amount of time and energy in order to change the standard, accepted explanation, the dogma of the day, within a scientific context,” remembered Arnie in that interview with Dr. Atala.
Arnold Caplan was granted his Ph.D. in 1966 for studying the inner and outer mitochondrial membranes. For his postdoc, Arnold and Bonnie moved to Boston where Arnie joined Professor Nathan O. Kaplan, chairman of the Department of Biochemistry at Brandeis University.
Reparative Cells of the Mesenchymal Lineage
At Brandise, as Caplan told Atala in their interview, “Professor Kaplan had previously published the effects of nicotinamide and its analogs and the formation and functioning of NAD/NADH. In the literature, I found other publications in which analogs of nicotinamide caused teratology in developing chick embryos: one group of molecules caused muscle defects and another group of molecules caused bone and cartilage defects.”
“My naïve idea was to initially set up a culture of developing embryonic chick skeletal muscle cells as described in the 1960s by Irwin R. Konigsberg and coworkers and expose these cells to the teratogens and to unravel the biochemical mechanism of action in the myogenic developmental process in cell culture.”
“To accomplish these experimental objectives, Nate Kaplan introduced me to a wonderful gentleman, Professor Edgar Zwilling in the Biology Department, who agreed that I could work in his laboratory to establish this culture system and run my experiments. I did not know Zwilling from a hole in the wall and I had never read any of his classic papers in the mid-1950s involving the development of embryonic chick limb buds.”
It was in Zwilling’s laboratory in 1967 that Arnold developed a way to isolate the undifferentiated mesodermal cells from the developing embryonic chick limb buds. This system allowed him to study the ways in which cartilage, bone, and muscle cells differentiate from embryonic limb bud cells in culture. Arnold’s resulting paper was published in 1968 in the journal Science.
Arnold demonstrated that the external concentration of nicotinamide in cell culture controlled the cytoplasmic concentration of NAD, which eventually involved the PolyADP-ribosylation of histones as the cells were differentiating.
That work established Dr. Arnold Caplan as an emerging thought leader and developmental biologist who, in 1969, was recruited by the Biology Department of Case Western Reserve University to teach their long-standing courses in Developmental Biology and Embryology.
Caplan Meets Urist…and Defines Mesenchymal Stem Cells
The official unveiling of the now ubiquitous concept of mesenchymal stem cells was in 1991 when Dr. Caplan’s paper was published in the Journal of Orthopedic Research.
But the idea of mesenchymal stem cells took root about 15 years earlier when Dr. Arnold Caplan met the inimitable Professor Marshall Urist.
From that same Atala interview with Caplan, here is how Arnold remembers the moment. “In the late 1970s, I was mesmerized by a lecture given by Professor Marshall Urist, M.D., on the effects of demineralized bone and the formation of de novo new bone in the muscle pouch of adult mice. Marshall Urist was an orthopedic surgeon at UCLA with an innovative and inquisitive mind.”
“He deduced that inductive molecules must have leached out of the demineralized bone and stimulated progenitor cells to form bone in this abnormal site. He named these factors bone morphogenetic proteins, or BMPs, and spent many years trying to purify these molecules from demineralized bone.”
“I joined the race to purify these molecules and developed an assay for molecules found in a high-salt extract of demineralized bone. The extracted factors were placed into the medium that bathed cultures of undifferentiated embryonic limb bud cells; these extracts caused the cells to form cartilage under conditions where cartilage never usually formed (a study that we published in Developmental Biology in 1985). My laboratory then tried to purify these molecules and, indeed, we were competitors and in a race with my good friend Marshall Urist.”
“I was intrigued by the original Urist observation and concept that there must have been a receptive cell in the adult mouse muscle that responded to the BMPs. Steven Haynesworth, Ph.D. (a postdoctoral fellow in my lab), and I started to purify culture adherent cells from fresh scopes of human bone marrow (known to have osteochondral progenitors) which could be expanded and induced into the cartilage and bone lineages in culture.”
“The unique trick to this new technology was the use of the optimized culture medium (selected batches of fetal calf serum) which had been previously used with the embryonic chick limb bud cell cultures. Because of the mesodermal origin of the embryonic chick limb bud cells, I called these adherent human marrow cells mesenchymal stem cells (MSCs), because we could cause them to differentiate into mesenchymal phenotypes in culture and coined the term in a publication in the Journal of Orthopedic Research in 1991.”
END OF PART I:
PART II: “Becoming the Father of Regenerative Medicine” will appear in the next edition of Orthopedics This Week
