It was important to us to do a blog on the current state of Stem Cell Research. We have witnessed the disappointment of many in the community based on the current “Clinical Hold” that has been put on the SMA clinical trial. It is important to point out The Sophia’s Cure Foundation has supported and will continue to support Stem Cell Research. We believe Motor Neuron Research is part of the big picture in regards to Spinal Muscular Atrophy. Eventually Motor Neurons will have to be replaced to correct the loss of Motor Neurons in our children. I think it is important for the community to understand the recent correction that has taken place in regards to this field of research. Currently there are some major hurdles that must be overcome before Stem Cells can replace Motor Neurons that have been lost. What is a possibility for Stem cells is to offer Neurotrophic Support. This suggests that Stem Cells could possibly help existing motor neurons, but it is not replacing motor neurons that have been lost. This tends to be reflected in mouse data. In mice with Spinal cord injury there was an improvement in condition. The motor neurons are still there and can be “helped” or “supported”. In the SMA Type 1 mouse model the motor neurons have been lost and an increase in lifespan was not witnessed. I think it is important for people to keep an open mind and ask questions about research. Although the vast majority of us are not Nascar competitors…….we can still understand the basic principles of the road and can safely operate an automobile. I think the same holds true for the basic principles of research. I am thankful to live in a country where the judgement in court is not based off of whether the plaintiff or the defendant has more experience but rather which party is able to better prove their case by substantiating their claim by use of data and evidence.
It appears to me that there are 2 major hurdles that must be overcome prior to Stem Cells becoming a viable treatment for SMA. The first part of the equation is stem cell diversification. When we hear of motor neurons many of us assume that there is a single type of motor neuron. This is clearly not the case. There are hundreds of specific types of motor neurons that are required in a figure as complex as the human body. Some estimations are 900 or more different kinds of motor neurons. There are specific neurons that control specific muscle groups. Without this complex make up of diverse motor neurons the spinal cord would resemble that of the most basic vertebrate. Scientists are unable to properly innervate motor neurons in a mouse model, so what they did was knockdown a gene in mice that controls motor neuron differentiation which caused the spinal cord to revert back to a primitive state. This was described in a recent article published by the Howard Hughes Medical Institute where they witnessed the necessity of genes to diversify motor neurons in a mouse model:
Jessell, Dasen, and Tucker demonstrated the significance of FoxP1 in mice by inactivating the gene and showing that the spinal cord lacked the full repertoire of motor neurons without it. “This mutation, in effect, reverts the spinal cord to a primitive ancestral state, generating a lamprey-like spinal cord encased in a mammalian body,” Jessell says.
The human body is very complex and we have control of movements that other animals do not. The various specialized movements require a larger diversification of motor neurons. The article also noted:
“In mammals, many hundreds of different types of motor neurons are needed to control the variety of muscle types used to coordinate movement.”
Scientists are at the early stages of beginning to understand this research. Advancements are being made as an article recently published from Universities of Edinburgh points out but we are just starting basic research in this complex area. There is a tremendous amount of work left to be done before we can create all of the different motor neurons in the human body and the exact placement of each of these motor neurons along the spine.
Once we figure out how to create these different motor neurons the next major hurdle is to figure out how to make them project out from the spine and make the synapsis with the proper muscle groups. These projections outward from the spine have not been extremely successful in a primate, a mouse, or even a chick embryo injected with stem cells. There is not a single Stem Cell Researcher in the entire world who has been able to create a full innervation in humans and can validate this with data. It would require a great leap of faith to believe that these stem cells would make the projections out from the spine, locate the proper muscle and create a proper synapsis in humans. It is important to understand that motor neurons make the connection from the spine and project outwards to attach to muscle when we are a fetus and while we are much smaller than a mouse. As we grow these motor neurons are stretched over the course of our lifetime to the great lengths they become when we are an adult. I have received a quote I would like to share:
“There has been some success in demonstrating subtle reinnervation of denervated muscle following stem cell implantation in mice, but it requires a considerable leap of faith to then assume that it will occur in humans. Infants with Type I SMA have motor neurons that are a several orders of magnitude longer than in mice. If I recall correctly, human motor neurons first connect to muscle in the first 8-10 weeks of fetal development (when we are smaller than a mouse) and the nerves literally ‘stretch’ as we grow and develop. So, even if stem cells can be implanted into the spinal cord and coaxed into becoming the right type of motor neurons, there is presently no evidence that they will be able to find their way across such vast distances to the correct muscle groups in human infants or adults. Of course, we should never say ‘never’ in science, but it is clear that there is still a lot of work to do before rewiring motor nerves can become a reality.
The more likely value of stem cells in the immediate term is their use in modeling the disease ‘in the dish’ not only to identify the pivotal biochemical processes that determine motor neuron life or death, but also to provide us with an efficient way of screening tens of thousands of potential drugs. If a compound keeps the human SMA motor neuron alive in the dish, it may keep the motor neuron alive in the patient. Of course there are no guarantees – such is the nature of research – but positive results in the lab would provide an impetus for taking compounds forward into clinical studies”.~Brian Dickie PhD Director of Research Development Motor Neurone Disease Association
I believe Motor Neuron Replacement can become a valuable piece of the puzzle for reversing the disease in the future. This field of research will require a great deal of time and money to become a viable treatment for children and adults suffering from Spinal Muscular Atrophy. If we can stop the progression now and prevent further motor neuron loss it will buy us the valuable time needed to allow Motor Neuron Replacement to become a realistic option for our disease. All research is a gamble, but there is a growing list of card players who are proof that taking educated risks can optimize the chances of a successful outcome.