SIX QUESTIONS TOP SURGEONS ASK ABOUT STEM CELLS (Orthopedics This Week)
- How do you know the viability of stem cells and their ability to express phenotypes?
- How can we use stem cells to prevent osteo-arthritis?
- What do stem cells do when they get into an arthritic joint?
- What is the right nomenclature?
- What are the standard ways to test that the cells will do what we want?
- What clinical infrastructure do we need to do proper clinical studies?
Bone morphogenic proteins were not a failure, but they didn’t live up to their promise. With that observation, Tom Einhorn, M.D., and George Muschler, M.D., opened up a very interesting seminar regarding the use of stem cells in orthopedics at the recently concluded Academy (AAOS) meeting in New Orleans. The lessons learned from BMP, in other words, can help guide physicians as they contemplate using stem cells in their practice.
In fact, these two top surgeons and scientists listed six basic questions which every practitioner should ask about so-called “stem cells”.
But first; here is a little background about these top physicians and researchers–Tom Einhorn and George Muschler.
Tom Einhorn, M.D.
Dr. Einhorn is Boston University’s Chairman of the Department of Orthopaedic Surgery and Professor of Orthopaedic Surgery, Biochemistry and Biomedical Engineering. He’s a graduate of both Rutgers University and Cornell Medical College. He interned at the University of Pennsylvania Hospital, completed his residency St. Luke’s – Roosevelt Hospital in New York City and did a fellowship at the Hospital for Special Surgery.
His research has focused on repairing and regenerating bone and cartilage as well as reconstructive surgery of the hip and knee and treating metabolic bone disease.
Dr. Einhorn is the former Chairman of the Orthopaedics and Musculoskeletal Study Section of the National Institutes of Health, President of the Orthopaedic Research Society, President of the International Society for Fracture Repair and Chairman of both the Committee on Examinations and the Council on Research and Scientific Affairs of the American Academy of Orthopaedic Surgeons.
Among his many awards are the Marshall R. Urist Award and the Alfred R. Shands, Jr. Award from the Orthopaedic Research Society, the Kappa Delta Award from the American Academy of Orthopaedic Surgeons, the Dr. Marian Ropes Physician Achievement Award from the Arthritis Foundation and the Marshall Schiff Award from the American College of Rheumatology. He is Deputy Editor for Current Concepts Reviews for The Journal of Bone and Joint Surgery, and serves on the Editorial Boards of The Journal of Bone and Mineral Research, Journal of Orthopaedic Research and Bone.
George Muschler, M.D.
George F. Muschler, was researching stem cells before it was fashionable and is one of a small handful of researchers who’ve defined therapeutic stem cells and their potential. When he is not serving as vice chairman of the Orthopaedic and Rheumatologic Institute in the Cleveland Clinic, Dr. Muschler sees patients requiring adult reconstructive surgery or treatment of fracture non-union among other musculoskeletal problems.
Dr. Muschler’s lab in the Department of Biomedical Engineering at the Cleveland Clinic has consistently led the way in researching adult stem cell biology, tissue engineering, and regenerative medicine. He’s director of the Clinical Tissue Engineering Center (CTEC) and also serves as co-director of the Armed Forces Institute of Regenerative Medicine (AFIRM), a national network funded by the Department of Defense and dedicated to accelerating better therapies to serve wounded warriors.
Dr. Muschler is a member of the American Medical Association, American Orthopaedic Association, Association of Bone and Joint Surgeons, Orthopedic Research Society, American Society for Bone and Mineral Research, International Society for Stem Cell Research, Tissue Engineering and Regenerative Medicine International Society, and International Society for Fracture Repair.
His undergraduate degree was in Chemistry from the University of Illinois. His medical degree is from Northwestern University School of Medicine. His residency was at the University of Texas Southwestern Medical Center in Dallas, Texas. Like Dr. Einhorn, he completed a fellowship at the Hospital for Special Surgery. After HSS, Dr. Muschler went on to complete an additional fellowship at the Memorial Sloan Kettering Cancer Center.
Six Stem Cell Questions (commentary by RRY)
1. How do you know the viability of stem cells and their ability to express phenotypes?
Let’s face it. If you’re planning to put these cells into painful joint or disc, you’re sending them directly into a hypoxic and harsh line of fire. Even worse, transporting your stem / progenitor cells from point A (like a donor or bioreactor in Kalamazoo) to point B (your patient in Bakersfield) can cut the herd pretty significantly.
This is a tough, but critical question. Direct injection is the clinically preferred method to transplant cells and, for sure, the clinical studies of the past decade have clearly shown that these stem and progenitor cells have immense potential to improve tissue and organ function for multiple debilitating diseases and injuries.
But moving from the hot house of a well-controlled study to the real world of a busy clinic is not so easy. At a minimum, physicians need to find ways to improve the viability of cells after implantation. Many studies, including some from both Einhorn and Muschler’s labs, have correlated symptomatic relief with higher cell viability after transplantation. Cell injection procedures can kill lots of cells. Some studies have reported that as few as 1%–32% of cells survive post-transplantation.
2. How can we use stem cells to prevent osteo-arthritis?
Top researchers are increasingly concluding that “stem cells” are not the main event but rather part a multi-dimensional therapeutic solution.
Osteo-arthritis is caused by any number of triggers including mechanical and oxidative stresses, aging or apoptotic chondrocytes. Biologists who study these biologic processes point to articular chondrocytes within diseased cartilage as main actors. Specifically there are a couple of nasty little buggers in the knee called matrix metalloproteinases (MMPs) and aggrecanases which don’t just degrade the cartilage, they also contribute to a toxic joint environment. Stem cells have been shown in animal and some human studies to inhibit inflammation and to help restore damaged cartilage. But the results, while promising, are also a little confusing. Bottom line: “Stem cells” may well be but one component of a more complex treatment program.
3. What do stem cells do when they get into an arthritic joint?
If only we had a super slow motion camera to film these cells in action. The best thinking today about what stem cells do comes from Mark F. Pittenger, Ph.D., – whose 1999 paper “Multilineage potential of adult human mesenchymal stem cells” is probably the most cited stem cell paper ever (as of April 8th, 15,604 citations). In 2004, he wrote the following about stem cell activity for the journal Blood (Human mesenchymal stem cells modulate allogeneic immune cell responses);
In his study “hMSCs (human MSCs) altered the cytokine secretion profile of dendritic cells (DC), naive and effector T cells and natural killer cells to induce a more anti-inflammatory or tolerant phenotype. Specifically, the hMSCs caused mature DCs type 1 (DC1) to decrease tumor necrosis factor α (TNF-α) secretion and mature DC2 to increase interleukin-10 (IL-10) secretion; hMSCs caused TH1 cells to decrease interferon γ (IFN-γ) and caused the TH2 cells to increase secretion of IL-4; hMSCs caused an increase in the proportion of regulatory T cells (TRegs) present; and hMSCs decreased secretion of IFN-γ from the NK cells.”
Simply put, Dr. Pittenger is saying that MSCs reduce inflammation and lay the foundation for tissue regeneration and repair.
4. What is the right nomenclature?
What is color? Same problem with the word “stem cell”. You and I can tell what is “blue”. Scientifically, however, the color blue is a set of wavelengths in the electromechanical spectrum somewhere between 430 and 790 THz. There are more colors within that range than one person can count in an afternoon. Same for “stem cells”. So-called “stem cells” are actually progenitor cells which exist on a very wide spectrum of potentiality. The total number of cell types which could be progenitors or express growth factors or in some manner act like the cells described in Dr. Pittenger’s paper probably number in the hundreds of thousands.
Calling these cells “stem cells” is like saying every color is blue.
The nomenclature or the names we use to describe these cells does not really describe their true capabilities or functions.
5. What are the standard ways to test that the cells will do what we want?
First of all, “stem cells” are loaded with a wide range of expectations from patients, sales people and physicians. What patients want is to get back to normal. What physicians want is something safe and effective and affordable. Step one is figure out the base line expectations for these progenitor cells. Is it fair to expect either off the shelf, cultured MSCs or autologous progenitor cells to stop and reverse osteoarthritis? No. Is it fair to expect them to behave along the lines described in Dr. Pittenger’s paper? Yes, as adjusted for each patient’s biology and the broader eco-system of their joint. Safety first. Then pain relief. In stages, led by the data, build to a standard way to test how one or more of these progenitor cells perform. No question, there are lots of moving parts in this puzzle.
6. What clinical infrastructure do we need to do proper clinical studies?
Well, first there is the issue of money. Then we could try to clone a few of the key researchers like Muschler, Einhorn and Pittenger and sprinkle them around the country in about 100 clinics. But, perhaps most important (or 2nd after money), is a data infrastructure which would support a comprehensive, complete, longitudinal registry and would have the support of most patients, clinicians, health systems, and payers in the research process.
What clinical infrastructure do we need? We need money. Researchers like Muschler, Einhorn and Pittenger. And a massive comprehensive longitudinal data registry.
Simple.
And a great dream.