fundraising $1,000,000 in seed money to eradicate ALS
The Jim Himelic Neuromuscular Research Laboratory
On May 20th, 2004 the University of Arizona officially named the Stem Cell Laboratory in the Department of Neurology at the University of Arizona College of Medicine “The Jim Himelic Neuromuscular Research Laboratory” (Video of dedication). Dr. Bruce Coull, Dr. Timothy Miller, and Dr. Jonathan Flax dedicated the laboratory to the Himelic family in return for all the funding received through the Himelic Fund. With all proceeds from the annual event going directly to the U of A, these doctors are able to research ALS and other neurological diseases and carry out clinical trials.
The Himelic Fund for ALS Research Brochure (pdf file)
KUAT/PBS story on ALS research at the U of A
Jim Himelic Neuromuscular Research Laboratory Long Term Goal
Differences Between a Mature and Immature Nervous System
The Possibilities of Mature NSCs and Its Ramifications on ALS
Jim Himelic Neuromuscular Research Laboratory Research Focus
Jim Himelic Neuromuscular Research Laboratory Approach
Status of ALS Research in Other Laboratories
Jim Himelic Neuromuscular Research Laboratory Long Term Goal:
Acquiring the ability to force neural stem cells (NSCs) to alter into motor neurons and replace those lost in ALS patients.
NSCs are located in the spinal cord and brain from the earliest times of development through adulthood. NSCs are the key stem cells from which the entire nervous system is derived.
Differences Between a Mature and Immature Nervous System
In an immature or developing nervous system, NSCs have the capacity to generate all the subtypes of neuronal cells (motor neurons, cortical neurons) and glial cells (cells that support neural survival and function). Following injury or neural degeneration, the immature nervous system can compensate by directing NSCs to replace any and all cell-types that have been lost.
Studies have shown that the ability of NSCs to build neuronal cells for the brain and spinal cord diminishes with age. As the nervous system matures, specific types of neuronal cells produced by NSCs are carried out in a strict order. Once a particular type of cell has all the required neurons generated, the NSCs move on to the next cell type and are no longer able to go back and generate that specific cell again, regardless of injury or any other type of defect causing that type of cell to diminish in number. After all the neurons are generated, the NSCs switch to producing exclusively glial cell types (non-neuronal cells).
The Possibilities of Mature NSCs and Its Ramifications on ALS
NSCs have the potential to form new neurons in mature nervous systems. If endogenous NSCs, stem cells already located in the body, can be reverted back to their earlier state and be forced to differentiate into neuronal cells and replace those lost in patients, the effects of ALS can be slowed or possibly even reversed.
Utilizing endogenous NSCs would side-step many of the scientific and political hurdles associated with exogenous NSCs. Besides the technical difficulties of transplanting stem cells throughout the brain and spinal cord, the issues of rejection by the host in addition to the possibility of inadvertently introducing a foreign cell that may contain a virus are formidable. Also, an endogenous approach avoids the entire political and religious debate surrounding the medicinal use of embryonic stem cells.
Jim Himelic Neuromuscular Research Laboratory Research Focus
1) To understand and overcome the intrinsic blocking of adult spinal cord NSCs that prevents them from undergoing motor neuron differentiation.
2) The complete characterization of the functions of two identified packaging proteins responsible, in part, for this blocking within the next year.
Jim Himelic Neuromuscular Research Laboratory Approach
The first step of the lab is to determine the mechanisms that begin to restrict the ability of NSCs to become motor neurons as the nervous system matures. Currently, the doctors are focusing on how late spinal NSCs switch from the immature state to the mature state. Other labs have found that there is an intrinsic blocking mechanism in late spinal NSCs that prevent them from being directed by foreign signals. In the last 2 years, the lab has found that NSCs in older animals also have an active block to becoming motor neurons. This block appears to be, in part, due to a change in the physical structure of the genes that direct NSCs to differentiate into neuronal cells. The change stems from the way in which the genes are packaged by its surrounding proteins.
This packaging encases the genes in a protein coat and wraps them in a tight bundle such that they can’t be effectively turned on. If the genes can’t be turned on, the NSCs can’t be turned into new motor neurons. Fortunately, this gene packaging is potentially reversible. If the packaging can be removed, the genes can be turned on and adult NSCs can produce new motor neurons. Identifying the key molecular players that mediate this gene packaging (gene silencing) is the required first step for the laboratory.
Two proteins that play a key role in this process have been successfully identified. The first packaging protein operates early in embryonic development and appears to regulate NSC differentiation by silencing genes that direct alternative choices (i.e., by closing off alternative fate choices, the available options for an NSC become limited). The second protein is involved in orchestrating the formation of neural circuits (including motor neurons) during development. Initial findings at the lab suggest that this second packaging protein may silence alternative choices of circuits. Because motor neurons are required to make correct connections with both muscle and other neurons, understanding and reactivating the genes that establish the circuitry within the motor neuron may be critical for adult NSC-derived motor neurons to become functional.
Molecular tools have been developed to modulate the activity of these packaging proteins and testing will be done to see if elimination of these packaging proteins will allow for NSCs to being forming motor neurons. If initial approaches are successful, clinical partners will be established to push forward with human clinical trials.
Status of ALS Research in Other Laboratories
Neurologists in other research laboratories are currently focusing on identifying the genes which cause familial ALS (FALS), responsible for approximately 10% of all cases, and understanding how these mutant genes cause the disease and how this pathologic process may be related to spontaneous ALS (SALS). Scientists have identified four genes responsible for or which predispose individuals the FALS. In addition to these identified genes, there are a number of genetic loci that harbor yet to be discovered FALS-causing genes. Given that many of the features of FALS and SALS are similar, discovering how these mutations cause FALS may shed light on how SALS occurs. However, the majority of SALS cases don't appear to be due to these known mutations.
Exciting research from other laboratories focuses on differentiating embryonic stem cells (cell lines derived from fertilized mouse and human eggs) into motor neurons, and transplanting these cells into animal models of ALS. Recent work from the Rothstein and Kerr Laboratories have demonstrated that embryonic stem cells in a culture dish that have been ordered to differentiate into a motor neuron fate then subsequently transplanted into the spinal cord of rats, which have previously had their motor neurons destroyed by a virus, are able to mature and survive in the spinal cord. In addition, when chemicals that allow axons to grow in the adult spinal cord are used in combination with NSCs an attractant for the motor neuron axons is produced. Placed in the peripheral nerve roots, these embryonic stem cell-derived motor neurons make functional connections with the muscle, partially reversing paralysis.
In addition to research on FALS, developing targeted therapeutic approaches to these disease processes and testing them in both animal and human trials continues to make progress. The Koliatsos Laboratory has transplanted human NSCs into the spinal cords of ALS mice, and their researchers have demonstrated that the engrafted cells differentiated into neurons. Their research also has shown that those animals with engrafted cells showed later onset and a slower progression of the motor neuron disease and lived longer compared with control animals. Thus, transplanted NSCs also have demonstrated therapeutic efficacy. This supports the idea that the differentiation of endogenous NSCs into neurons may offer significant therapeutic benefits.
How You Can Help
With this cutting edge research, scientists hope that the eradication of ALS will be a possible and hopefully even a probable goal that can be attained within most of our lifetimes. A neuromuscular research facility with a primary focus on Amyotrophic Lateral Sclerosis capable of holding stem cell experiments requires highly specialized and expensive equipment and supplies.
With your financial assistance making the creation of such a facility possible, the University of Arizona will become a forerunner in the research to help fight and cure ALS. For questions or comments regarding the laboratory, please contact the Jim Himelic Foundation at info@jimhimelicfoundation.org
Learn More About ALS
To Learn More about ALS please refer to the following links:
Muscular Dystrophy Association ALS info
Duke's Richard Bedlack, MD, PhD, "ALS-Recent Advances" Presentation Given at the U of A
Research paper by the U of A Department of Neurology (PDF document)
