Cell Conversion: Potential Solution for Neurodegenerative Diseases

About 10 percent of the genes in the human genome encode transcription factors. Transcription factors are proteins that bind to DNA, controlling gene expression. Notably, they control the precisely-timed differentiation of stem cells into specialized tissues during the development of organisms.

In an article published online in the journal Nature this week, Marius Wernig and colleagues at Stanford University demonstrate that the expression of only three transcription factors, that is Ascl1, Pou3f2 and Myt1l, is needed to convert cultured fibroblasts, that is undifferentiated connective tissue cells, into nerve cells (Vierbuchen and others, 2010). The cells were shown to produce action potentials, i.e. the electrical discharges that propagate along their output processes called axons, and formed functional connections, known as synapses, with other nerve cells.

Although the conversion has been successfully carried out only in a dish with developing mouse tissue and only the most essential nerve cell functions have been demonstrated, the method does not utilize stem cells and still may bear great potential for therapies, seeking to replace lost nerve cells in neurodegenerative diseases, e.g. Parkinson's disease.

Addendum

• If you are considering stem cell therapy, you may find the information on the International Society for Stem Cell Research site helpful (07/26/10).

References

• Vierbuchen T, Ostermeier A, Pang ZP, Kokubu1 Y, Südhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature: online.

Related Posts

• Recent Advances in Parkinson's Disease

Recent Advances in Parkinson's Disease

Two days ago, National Public Radio's  All Things Considered broadcast a segment in its series This I believe with Mohammed Ali's contribution entitled "I Am Still The Greatest". The great boxing champion is suffering from Parkinson's disease. But that did not stop him to deliver his testimonial. Despite his condition, Muhammad Ali has risen to even greater championship after his boxing career ended, becoming a relentless ambassador for humanitarian causes and for more research in better treatments for this horribly destructive disease.

Parkinson's Disease is a degenerative disease of the central nervous system, resulting in severe tremor of limbs, motor arrest, and disruption of speech. Its cause is unknown, though a subset of people with the disease are known to carry an inherited genetic mutation that may predispose degeneration.

Nerve cells located in the basal ganglia, a group of forebrain structures situated nose-ward under the cerebral cortex, control our fine movements. They provide feedback to the nerve cells in the motor areas of the cerebral cortex that connect with nerve cells in the ventral horn of the spinal cord. The spinal nerve cells, known as motor neurons, innervate muscle fibers and control limb movement.

Basal ganglia functionality depends on a set of nerve cells located in a structure behind the basal ganglia, known as substantia nigra. In Parkinson's disease, the substantia nigra cells degenerate over decades and eventually die. The loss of their input to the basal ganglia perturbs motor control.

The nerve cells in the substantia nigra use the neurotransmitter dopamine to communicate with the nerve cells in the basal ganglia. Replacing the lost dopamine with the systemic administration of the drug levodopa ameliorates the symptoms. However, over time the brain develops increasing tolerance to the drug, and even high doses cannot control tremors anymore. Efforts pioneered by A. Björklund at the University of Lund in Sweden at grafting into the brain undifferentiated cells induced to produce dopamine showed promising results in animal studies, but grafts with fetal ventral mesencephalic tissue, rich in dopaminergic neuroblasts, have not proved unequivocally successful in humans (Kefalopoulou and others, 2014).

When medication eventually fails, surgically removing specific parts of the basal ganglia or inter-brain structures also involved in fine motor control may improve the condition (Çoban and others, 2009). In the last decade, however, deep brain stimulation has gained popularity. The method is less invasive and has produced superb outcome. It entails electrical stimulation of nerve cells in the basal ganglia or the inter-brain using thin implanted micro-electrode wires. The electrical impulses are thought to disrupt the persistent nerve cell activity causing the tremors. As a potential further improvement of this procedure, a research study published recently in the journal Science showed that the electrical stimulation of spinal cord nerve fibers with micro-electrodes, threaded between the vertebrae to touch the outer spinal cord where bundles of nerve fibers run that convey sensory information to the brain, may suffice to subdue tremors in Parkinsonian mice (Fuentes and others, 2009). The promising findings were reported on Mar. 19, 2009, in Julie Steenhuysen's post entitled "Spinal cord device helped mice with Parkinson's" on Reuters and Sandra Blakeslee's article entitled "Spinal Shocks Ease Parkinson’s in Mice" in The New York Times. If this procedure proved successful in people, brain surgery would be rendered unnecessary.

If Parkinson's disease runs in your family, you may be interested in gene chip tests for a predisposition available from 23andMe.

Addenda

• Some patients with Parkinson's Disease benefitted from having fetal midbrain tissue rich in dopamine-producing nerve cells grafted into the dopamine-depleted basal ganglion known as striatum. However, dyskinesias, that is severe bouts of involuntary movements, hampered recovery despite major improvements in motor control. Using radioactively labeled markers and Positron Emission Tomography, Politis and others (2010) recently showed that the grafts produce extraordinary amounts of the neurotransmitter serotonin, suggesting that excessive serotonergic innervation of the striatum causes the dyskinesias. Hence, medication with long-lasting serotonin antagonists may subdue the undesired effect in grafted patients, and the use of grafts that lack great amounts of serotonergic nerve cells in future surgery may improve outcome in implantation therapy (07/03/10).
• If you are considering stem cell therapy, you may find the information on the International Society for Stem Cell Research site helpful (07/26/10).
• Today, Diane Rehm interviewed Miguel Nicolelis on her show with the title "Miguel Nicolelis: 'Beyond Boundaries'". Dr. Nicolelis is a lead investigator in this research and discusses his fascinating insights (03/16/11).
• Kefalopoulou and others (2014) report that 2 of the 18 patients who volunteered for the University of Lund trial implanting grafts of fetal ventral mesencephalic tissue 15 and 18 years ago showed significant, persistent behavioral improvements (04/09/2014).

References

• Çoban A, Hanagasi‌ HA, Karamursel‌ S, Barlas‌ O (2009) Comparison of unilateral pallidotomy and subthalamotomy findings in advanced idiopathic Parkinson's disease. Br J Neurosurg 23:23-29.
• Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA (2009) Spinal cord stimulation restores locomotion in animal models of Parkinson's disease. Science 323:1578-1582.
• Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Rehncrona S, Bjorklund A, Lindvall O, Piccini P (2010) Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci Transl Med 2(38):38ra46.
• Kefalopoulou Z, Politis M, Piccini P, Mencacci N, Bhatia K, Jahanshahi M, Widner H, Rehncrona S, Brundin P, Björklund A, Lindvall O, Limousin P, Quinn N, Foltynie T (2014) Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol 71:83-87.

More Literature
with

Related Posts

• Cell Conversion: Potential Solution for Neurodegenerative Diseases

Faith & Science

Once in a while in the fall, the Holy See convenes a scientific meeting at the Vatican. Reuters filed a report on this year's event on Oct. 31. The current theme is "Scientific Insights into the Evolution of the Universe and of Life." The Holy See seeks to showcase eminent scientists and Nobel Prize-laureates who pursue research deemed of particular importance to the Church. Last Friday, Oct. 31, the physicist Stephen Hawking, author of "A Brief History of Time From The Big Bang To Black Holes", spoke about his insights into the evolution of the universe. Though, the head of the Pontifical Academy of Sciences at the Vatican presides over these conventions, the Holy Father himself usually addresses the assembled and gives his blessing. No doubt, the Catholic Church takes science seriously.

I attended this meeting twenty years ago. I am not Catholic. I went regardless. The theme was "Longevity and Quality of Life." Advances in the understanding of nerve cell repair after brain injury were presented. I am interested in brain plasticity. John Paul II was pope. A pharmaceutical firm named Fidia from Abano Terme, a beautiful spa in Italy, co-sponsored the convention. Fidia-supported research had provided evidence that gangliosides were involved in nerve cell repair after spinal cord injury and the company would apply for a U.S. patent for gangliosides as therapeutics in coming years. The hope at the Vatican meeting was that research on the role of gangliosides might eventually yield potential remedies for neuro-degenerative diseases. Sadly, not much has come of this hope. Fidia's fortune evaporated in a political scandal involving the bribery of high-ranking Italian government officials.

Little did we know how important this type of research would become to John Paul II personally. He passed away three years ago after a long struggle with Parkinson's Disease. Perhaps he knew at the time. Close up, this pope was strikingly warm and personable. He seemed to care about people. I was deeply moved by the reverence he was paid. I saw him with mixed emotions. I shared a number of his passions, not the least his love of skiing and hiking in the alps, particularly in the Mont Blanc massif near Courmayeur high up at the source of the Aosta. There you may visit the Val Veny, the Punta Bronner, the Val de la Fenetre, the Mont Dolon. The views are spectacular. He traveled there on one of his last trips, sat on the deck of his favorite spot, and watched these magnificent mountains for hours on end. When I saw the pictures of him reposing in a chair, studying the panorama in solemnity and silence, I immediately understood. He had a passion for life. However, many consequences he drew from this passion I could not agree with.

Before I left for this trip, a colleague and friend told me that a pendant of the Virgin Mary worn during the papal blessing would protect you from harm for the rest of your life. I bought a pendant in one of the numerous religious nick-knack shops on the ascend to St. Peter Square and took it to the blessing. Two days later I returned home, carrying with me a blessed pendant for my friend and the insight that the Holy See strives for and cares deeply about an understanding of science as a method of enlightenment.

Addendum

• As Philip Pullella reports in his post on Reuters dated Jul. 2, 2009, the Holy See embraces scientific discovery, only on its own pace (07/02/09).

Related Posts

• Recent Advances in Parkinson's Disease