Much new scientific research requires a battle with society before it matures into an accepted branch of science. Body snatchers robbed graves to supply cadavers for dissection, paving the way for anatomy just over 200 years ago.
Over the past few decades, stem cell science in the U.S. has had to leap over many obstacles including gaining public and governmental support, and satisfying regulators that had little experience with how to regulate this new field.
The good news is that the tide is changing. Public and governmental support has increased. A poll published in the New England Journal of Medicine has shown that a majority of Americans believe that medical research involving stem cells obtained from human embryos is morally acceptable. The U.S. Supreme Court has recently dismissed a case that had suspended government funding of projects involving embryonic stem cells. As a result, financial support from the government is now available.
The real boost is that three applications for testing embryonic stem cell therapies in clinical trials have received the go-ahead by the U.S. Food and Drug Administration (FDA). These are focused on spinal cord injury, age-related macular degeneration, and Stargardt's macular dystrophy.
The first milestone occurred when the FDA granted permission to the biotechnology company Geron to initiate the world's first human clinical trial of an embryonic stem cell-based therapy for acute spinal cord injury. This happened three years ago under the leadership of CEO Thomas Okarma.
But it has been a rollercoaster ride ever since. Soon after, the company reported the observation of non-proliferating microscopic cysts in some animals to the FDA and trials were put on hold. After additional experiments that addressed concerns, approval was granted once again. But the volume of regulatory documentation prepared for the FDA (over 21,000 pages) plus time delays and increasing financial burdens had their toll.
One year later, in 2011, a decision to halt the trials was announced due to changes in company strategy and finance. Hope for stem cell therapies overall was crushed. But Okarma, who subsequently left the firm, was not deterred. He has resurfaced at a company called BioTime with a new tactic to drive his previous efforts. In January this year, he signed a definitive agreement to obtain the intellectual property and other assets associated with Geron's discontinued human embryonic stem cell program, including the early phase clinical trial for this product. Once again Okarma is in the driver's seat.
What's the science behind the product?
Stem cells are remarkable cells. They are the crucial link between the one cell, the fertilized egg that begins a life, and the final individual. The fertilized egg divides to form embryonic stem cells. The defining properties of these cells are their ability to self renew and form more stem cells, and their ability to produce cells that are committed to a specific cell lineage such as muscle. They have the ability to form all of the cell types in the body. It is this ability that gives them great potential as a therapy.
During spinal cord injury, nerve cells are damaged and often lose an insulating material called myelin sheath. The myelin sheath is needed to transmit nerve impulses. Geron used human embryonic stem cells to produce a cell line called GRNOPC1 that is committed to produce specialized cells called oligodendrocytes. Oligodendrocytes support nerve cells and produce myelin sheath and thus should help repair spinal cord injury.
The production of stem cells as a therapy is much more complex than the production of a drug. Geron's product required three stages: growth and expansion of cells from a stem cell bank, differentiating the cells to form GRNOPC1 cells (oligodendrocyte progenitor cells), and formulation for an "off-the-shelf" quality-controlled product (cells are cryopreserved). The therapeutic application of these cells is to implant them into patients to treat spinal cord injury.
Hundreds of preclinical experiments in mice demonstrated safety and showed biological and clinical effects such as production of factors that support neurons (neurotrophic factors), improvement of movement and ability to bear weight and myelination of axons. Concerns over stem cell-derived products focus on possible contamination with undifferentiated cells and formation of tumors. But there was no evidence of tumors in over 400 treated animals. Another encouraging result was that the cells remained within the boundaries of the original site of injury. A special device to deliver the cells into humans was invented.
At last, five patients have been treated in a Phase 1 clinical trial. Final data collection for the primary outcome is due later this month.
Continuing this research is a most ambitious project, but it has a record of good science and experimental evidence that give its scientists the confidence to go ahead. In so many ways, it is a success already, and has broken many barriers for others to follow. The work and determination of Thomas Okarma will be marked in the history of science.
On the horizon
The discovery that adult mature cells, such as skin cells, could be experimentally reprogrammed to form embryonic stem cell-like cells called induced pluripotent stem cells (iPSCs) in 2007 has been a great breakthrough that already has been acknowledged by a Nobel Prize. Reprogramming requires the introduction of several specific genes or small molecules into the adult specialized cells.
The ability to obtain embryonic stem cell-like cells without the need for embryos will greatly advance the understanding and application of stem cells. In addition, the generation of iPSC cells from patients with diseases will enable improved models of disease and drug testing. Such cells have been produced from patients with Huntington's Disease, juvenile diabetes, and severe combined immunodeficiency.
Pushing ahead, Advanced Cell Technology is seeking the go-ahead from the FDA to initiate the first clinical trials using the iPSC-derived cells later this year. They plan to produce platelets that can be used for blood-clotting diseases.
It is time that stem cells gain their place in medicine.
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