Steppingstones: Four Milestones on the Path to Neurological Cell Therapy 

Source: Ole Isacson, MD-Ph.D., founding Director of the Neuroregeneration Research Institute at McLean Hospital, Professor of Neurology (Neuroscience) at Harvard Medical School, Professor of Neurology at Massachusetts General Hospital, Biorasi Scientific Advisory Board Member. 

Cell therapy and regenerative medicine are touted as the future of clinical research and patient treatment. More than a trend, today’s market sources predict a $100B cell therapy industry over the next seven years. Technically, though, this is not a new area – clinicians have been exploring the use of cells to prolong life and make “necessary repairs” to the human body for quite some time. 

“A degrading body is a fundamental truth,” noted Dr. Ole Isacson, founding Director of the Neuroregeneration Research Institute at McLean Hospital, Professor of Neurology (Neuroscience) at Harvard Medical School, Professor of Neurology at Massachusetts General Hospital, and Biorasi Scientific Advisory Board Member. 

“Pioneering physicians and clinicians have realized this inevitability and worked towards the goal of using the body’s building blocks (cells) to combat debilitating diseases. And with stem cell therapy expanding into Parkinson’s Disease and other neurological illnesses, it is important to look back on these early milestones of cell therapy in light of these new developments in clinical research.” 

Milestone 1: Blood Transfusions 

Red blood cells (RBCs) are the most common cell in the human body, accounting for 20 percent of all cells.1 Using blood as potential cell therapy for humans began in the 1600s, leading to the first successful transfusion – by James Blundell in 1818 – to treat postpartum hemorrhage.2 The transfusion process was further refined through the discovery of the various blood types, the separation of blood into its key components for easier use, and the development of safe and effective storage. 

Milestone 2: Transplants and Grafts 

Based on a patient’s disease state and severity, the effect of blood transfusions often lasts from a few weeks to a few months. In order to reduce the demand and frequency of transfusions, clinicians sought to develop a process that would kick-start the blood replication and replenishment process.3 

“This is when stem cells come into play,” noted Dr. Isacson. “Clinicians in the 1960s conducted research into hematopoietic stem cells located in the bone marrow of humans and other mammals. These cells are the progenitors of red and white blood cells and platelets.4 Today, stem cells continue to be harvested from bone marrow and are infused through a process similar to blood transfusions. And the best part is that the stem cells are imprinted with their point of origin and return to the bone marrow to restart blood cell production.” 

Beyond blood and stem cells, early clinical research delved further into cell and tissue transplantation. Skin graft origins started before the first century and successful “epidermic grafting” began to take shape in the late 1800s.5 Innovations carried over into the 20th century through New Zealand surgeon, Dr. Harold Gillies, whose facial reconstruction for soldiers injured in World War One became today’s plastic surgery.6 Skin grafts were most commonly taken from the patient’s own body sites. Xenografts from pigs and other animals were also used, but served as temporary solutions that would degrade and lead to infection in the long-term. 

Heart and other organ transplants have also benefited from further research into cell therapy. The first human-to-human heart transplant occurred in 1967, with the patient living 18 days after the procedure. Today, more than 3,500 heart transplants occur per year, and the post-operative lifespan averages 15 years. Xenotransplantation, or interspecies transplant, still remains an option due to supply and demand issues or the severity of the patient’s illness. With a higher organ rejection rate, animal organs and cells used for human transplantation can now be genetically modified to potentially improve graft and patient survival. 

Milestone 3: Early Stem Cell Research and Cell Therapy 

“Stem cells, such as those used in bone marrow transplants, have proven to be capable building blocks for other regenerative therapy treatments,” said Dr. Isacson. “Adult stem cells are more mature and specialized. Their cultivation and application is confined to specific cell replenishment and regeneration, such as blood cells, skin cells, and bone and cartilage. Islet cells taken from the islet of Langerhans in the pancreas follow a similar regenerative process, and can be transplanted into the liver to produce insulin for patients suffering from type 1 diabetes mellitus.” 

The discovery of embryonic stem cells (ESCs) led to even further innovation in clinical research. By collecting stem cells before they matured and differentiated into their specific type, researchers found ESCs to offer characteristics, such as growth and self-renewal, needed to explore regenerative medicine and tissue replacement. 

“However, ESCs are seen as controversial in that they are harvested from abortive human tissue and trespass into the possibilities of human cloning,” said Dr. Isacson. “Fortunately, other options became available through the work of Nobel Prize winning scientist, Dr. Shinya Yamanaka. In 2006, Dr. Yamanaka and his team developed induced pluripotent stem cells (iPS cells) from the adult stem cells of a mouse. These cells matched the form and function of ESCs, without being divisive, and could be edited to mirror a specific stem cell for regenerative treatment.” 

Stem cell research has also paved the way for personalized cellular therapy solutions beyond transplants of cell and tissue. This is most effective in CAR (chimeric antigen receptor) T Cell Therapy, an anti-cancer therapeutic focused on lymphoma, leukemia, and multiple myeloma. Starting with immune cell therapy in mice in the 1960s, CAR T Cell Therapy began to show further promising results as T cells were modified to introduce cancer-fighting cells into the human body. CAR T cell therapy also works side-by-side with stem cell transplants to prevent the possibility of infection and graft-versus-host disease. 

Milestone 4: Neurological Cell Therapy 

“It has been my career goal to drive neurological cell therapy research forward,” said Dr. Isacson, “especially for Parkinson’s Disease. Beginning in 1995, through numerous iterations of stem cells, my team and I sought to remake dopamine neurons to reduce and eliminate neurological symptoms. This started with the successful transplantation of GABA (gamma-aminobutyric acid) neurons. From these first pioneering steps, we have proved that stem cell derived neurons (developed from stem cells) can reverse functional deficits in animal and human models and create neurotransmission of basal ganglia, motor functions, and behavioral recovery.” 

In 1998, Dr. Isacson’s lab pioneered the theory that normal, midbrain dopaminergic neurons – cell groups of neurons that reproduce dopamine and are critical in the communication between nerve cells in the brain – could be developed from embryonic stem cells. In 2002, with further study into the connection between dopamine loss and Parkinson’s, Dr. Isacson’s team was the first to demonstrate the transplantation of dopamine into animal models for this disease. 

“Results in these mouse models exceeded expectations,” said Dr. Isacson. “They revealed the potential for repair in dopamine systems across donor species. However, despite the regenerative properties, immune suppression was still a necessary part of the studies in order to prevent neurotoxicity and inflammation. 

“We sought to eliminate the need for immunosuppressant in our 2009 research trials. Rather than rely on embryonic stem cells, we introduced human induced pluripotent stem cells (hiPSCs), cells derived from skin or blood cells that self-renew and can be reworked into neurons to treat neurological disorders.”7 

New Pathways for Neurodegenerative Disorders 

Dr. Isacson continues to explore neurological cell therapy solutions for Parkinson’s by leading human and animal clinical trials.  

“Cell therapy research continues to bring us closer to a more optimistic solution across all neurodegenerative disorders,” said Dr. Isacson. “It is a unique ecosystem that moves beyond the limits of small molecule or antibody therapy. While pharmacological treatment is shown to reduce the severity of Parkinson’s, cell therapy has shown the most promise in repairing and rebuilding neurons and glial cells within the central nervous system environment. 

“But scientific innovation can take us still further, setting our sights on the exploration into the feasibility of cell therapy and pharmacological combination therapy and creating stronger pathways for Lewy-body dementia, and even Alzheimer’s treatment beyond reducing the presence of amyloid plaques, or brain inflammatory disease. This road to discovery leads us to the promise of genomic therapy as well, correcting genetic material inside the cell in one application to produce a lifetime of therapeutic benefits.8 To reach these exciting next steps and milestones ahead, we need to persist in our efforts for research and development to treat and cure neurodegenerative disorders.” 

RESOURCES 

1 Cafasso, Jacquelyn. “How Many Cells Are in the Human Body? Fast Facts.” July 18, 2018, Healthline. 

2 Garcia, Kristen. “A Brief History of Blood Transfusion Through the Years.” March 10, 2016, Stanford Blood Center. 

3 Dresden, Danielle. “How Long Does a Blood Transfusion Take, and How Long Does it Last?” July 23, 2021, Medical News Today. 

4 The American Cancer Society Medical and Editorial Content Team. “How Stem Cell and Bone Marrow Transplants are Used to Treat Cancer.” March 20, 2020, American Cancer Society. 

5 Kohlhauser, Michael, et. al.. “Historical Evolution of Skin Grafting – A Journey Through Time.” April 5, 2021, Medicina (Kaunas). 

6 Kirby, Robert. “World War I: The Birth of Plastic Surgery and Modern Anaesthesia.” November 6, 2018, The Conversation. 

7 Soldner, Frank et. al. “Parkinson’s Disease Patient-Derived Induced Pluripotent Stem Cells...” March 6, 2009, Resource. 

8 Martier, Raygene, et. al. “Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock.” September 18, 2020, Neuroscience.