Translational Research: From Bench To Bedside

Robert Lipsky, Ph. D

          Have you ever taken a medication when you were not feeling well? How do we know it's effective against illnesses? What allowed it to go from the laboratory research setting to your medical cabinet?

          On October 18th, 2012 at George Mason University, my NEUR410 class attended a presentation lecture conducted by Robert H. Lipsky Ph. D, the Director of Translational Research in the Department of Neurosciences from Inova Fairfax Hospital. He discussed various topics relating to his translational research including warfarin (coumadin), clinical depression, and spinal cord injuries.

          What is translational research? Dr. Lipsky defined it as taking findings in basic research and rapidly moving them to medical applications to produce meaningful health outcomes, "bench to bedside."

Translational Research diagram

Warfarin chemical structure

          The drug warfarin is commonly used to prevent the formation of blood clots. Although it is a relatively safe treatment, warfarin affects individuals differently and in some cases may cause life threatening side effects such as a hemorrhagic stroke. This is known as pharmacogenetics, when an individuals' genetic differences of metabolic pathways affects their responses to drugs during both therapeutic and adverse effects. Dr. Lipsky suggested that individuals carrying a variation in the vitamin K epoxide reductase complex (VKORC1) gene and/or cytochrome P450 CYP2C9 gene will respond differently to warfarin. Those genes have a complex-dose relationship with warfarin and will affect the response of the drug on individuals who carry it. The VKORC1 and CYP2C9 genotype accounts for about 50 percent of the variation in response to warfarin thus acting as a biomarker for determining initial dose. If individuals are good drug metabolisers, they will be at a low risk of hemorrhage and if they are poor drug metabolisers, they will be at a higher risk. Those individuals must be monitored closely or not given warfarin at all. The approach Dr. Lipsky suggested was to start individuals at risk in a small dose and monitor their side effects while slowly increase their doses over time if they are able to tolerate it.

VKORC1, CYP2C9, and warfarin interaction

          Major Depressive Disorder (MDD), commonly known as clinical depression is one of the greatest problems and killers throughout history. It affects approximately 18.8 million American adults and the rate of clinically depressed children is increasing drastically. During a twin study, Dr. Lipsky stated 40-50 percent of MDD are gained through heredity. Other potential environmental risk factors include chilhood abuse and stressful life events, such as alcohol. Further studies on the occurrence of neuropsychiatric disorders in monozygotic and dizygotic twins showed the following being having the highest to lowest genetic impact on MDD: Huntington's disease, schizophrenia, alcoholism, social phobia, panic disorder, anxiety disorder, and neurotism. 

"I am now the most miserable man living... 

I must die or be better." -Abraham Lincoln, 

suffered life-long depression.

          As treatment for these conditions, Citlopram, an antidepressant from the selective serotonin reuptake inhibitor (SSRI) class, was administered. When that did not work, what happens then? Dr. Lipsky discussed the Sequenced Treatment Alternatives to Relieve Depression (STAR*D)Project, which tested individuals' serotonin transporter, specifically HTTLPR. The results concluded showed nothing that predicted a cure or response. However, it did suggest that individuals who were "poor responders" and expressed low serotonin transporter levels had S and Long G alleles.

Oscillating Field Stimulation (OFS) Device

        
          Dr. Lipsky also discussed the importance of researching new treatments for spinal cord injuries (SCI). SCI affects 250,000 Americans, 52 percent of which are considered paraplegic and 47 percent quadriplegic. 11,000 new injuries occur each year and 56 percent of it affects the ages between 16 and 30. The few treatments for SCI today include medications, immobilization techniques, and surgery. Because little progress have been made treating SCI, Dr. Lipsky has requested a grant to continue research on Oscillating Field Stimulation (OFS) Device.

         

Oscillating Field Stimulation (OFS) Device

          OFS is a device placed in an individual that sends an electrical current to the injured spinal cord to prevent the "die back" phenomenon of several neural pathways. It regenerates the spinal cord and promotes healing directed to neurological recovery. Although very little research has been done on OFS, data from the small study group that was collected showed tremendous improvement compared to the control group. After 15 weeks following implant, OFS improved sensation in complete SCI patients. This was measured by a pin prick and light touch. Other improved symptoms include improved bladder and bowel control, sex life, no UTI, and overall better physical therapy and rehabilitation outcomes. Despite the positive signs from this research, nothing is currently being done to further investigate OFS. The major roadblock is money because conducting more experiments like this will cost over several million dollars each.

          Translational research facilitates the process of basic science findings to practical application that ultimately enhance human health and well-being. The topics discussed above were just a few examples of this type of research. It is the driving force that translates laboratory findings to meaningful health outcomes. Dr. Lipsky's presentation on his research demonstrated the pros and cons of translational research. The major roadblock he and others face is, of course, money. His research on warfarin got us one step closer to understanding how the drug impacts different individuals depending on their genotypes. The new acquired knowledge of being able to identify some people who are more susceptible to serious side effects that others is a great accomplishment. The same goes for his findings regarding MDD and the S and Long G alleles. The most interesting part of his presentation, to me, was OFS and it's ability to alleviate acute SCI so effectively. I would like to see Dr. Lipsky succeed to receive a grant that will permit him to continue research in this field because it will be greatly beneficial to the millions suffering from SCI with no current effective treatment. It is because of the efforts of Dr. Lipsky and other scientists that transitional research will discover new scientific breakthroughs in the laboratory and apply it in the practical setting that will ultimately drive the human race forward.





References (images)
http://neuroscience.gmu.edu/system/person_images/1452/cropped/Robert-Lipsky.jpg?1305916700
http://www.umcutrecht.nl/NR/rdonlyres/EB1B29D9-F623-4245-B262-D79B7904D980/4902/transaltional3.jpg
http://www.medicalisotopes.com/structures/11072.png

http://ars.els-cdn.com/content/image/1-s2.0-S0049384806004373-gr1.jpg
http://upload.wikimedia.org/wikipedia/commons/f/fe/Abraham_Lincoln_seated,_Feb_9,_1864.jpg
http://www.healingtherapies.info/OFS.jpg
http://www.sci-info-pages.com/facts.html

Neuroplasticity and Parkinson's Disease

This PET scan reflects the decreased

dopamine activity of a Parkinson's

patient's brain (before and after)

compared to a normal person's brain.

Think of a hobby you enjoy doing and the satisfaction you get from it. That pleasant feeling you experience is directly correlated to dopamine levels and the substantia nigra in the brain. As you can imagine, diseases that cause a disruption in dopamine levels and affect synaptic plasticity in the substantia nigra would greatly affect an individual negatively, as seen in various neurological diseases. How can we further study these mechanisms and pathways to understand them better and potentially create new treatments?

A synaptic view of dopamine levels in a
              normal and a Parkinson's affected neuron.

  Dr. Kim Blackwell, from the Computational and Experimental Neuroplasticity Laboratory of the Krasnow Institute at George Mason University, held a lecture in my NEUR410 class regarding her research on the mechanisms involved in synaptic plasticity and it’s relation to diseases such as Parkinson’s and schizophrenia. The talk focused on dopamine, a neurotransmitter that affects brain processes that control movement, emotional responses, and the ability to experience pleasure and pain. A major brain structure that is involved with neuron containing dopamine is the substantia nigra. As Blackwell mentioned, the substantia nigra is located in the mid brain and is an important component involved with rewards, addiction, and movement. Decreased dopamine levels in the substantia nigra will affect that brain structure, inhibiting neuronal plasticity and as a result cause diminished motor function, emotional instability, and learning impairment; some of which are seen in Parkinson’s disease..

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According to Dr. Blackwell’s experiments, theta burst stimulation in post mortem brain slices showed strong positive correlation between synaptic plasticity and long term potentiation (LTP) and long term depression (LDP). In order to further differentiate these two pathways, Dr. Blackwell and her team observed the spatial and temporal signaling pathways. To determine if dopamine and calcium activated signaling pathways discriminate temporal patterns, they measured the following responses of molecules CKCam, PKA, pS831, and pS845 to theta molecules different from the brain’s normal 20 Hz. While only CKCam showed discrimination at the time, Dr. Blackwell later learned that it was not the only one because dopamine interaction with Acetylcholine activated Gq couple pathways and so were molecules 2AG (LTP), PKC (Chemical LTP), and endocanabonoid. She determined that the brain actually releases receptors that bind to those molecules. Dr. Blackwell specified temporal specificity even further and concluded that theta bursts enhances PKC more than 2AG which results in LTP because the PKC effect dominates. This suggests that PKC is essential for LTP so to confirm it, an experimental test was conducted. Chelerythrine, a PKC inhibitor, showed non-specific time dependent effects thus confirming PKC is needed for LTP. Learning, memory, and movement will be affected as these different molecules influence the plasticity of LTP and LTD synaptic models.

A deep brain stimulation (DBS) device for
               treatment of symptoms of Parkinson's disease.

In the future, Dr. Blackwell and her team plan to continue experiments ensuring characteristics of plasticity. Those studies will include dopamine dependent plasticity and models of how network activity changes during habit learning, dopamine depletion, and drug abuse. She did a very good job describing the work she is doing and had a funny sense of humor which kept the audience interested. Although there was a lot of information being presented, I did not fully understand it all immediately but the notes from her slides that I copied down were clear and straightforward which eased the understanding process later. Her research is definitely moving neuroscience to further understand the importance of specific molecules and their roles in mechanisms involving LDP, LTP, learning, memory, and movement. Although Dr. Blackwell's work covers more research, this lecture was heavily geared towards Parkinson's. Currently, there is medication therapy to replenish the lost dopamine and deep brain stimulation devices to treat symptoms of Parkinson's  but none are very effective long term and have numerous side effects. Dr. Blackwell's work may open new doors to how to we treat this disease. Perhaps through her research, a more effective drug will be discovered that treats the disease as well as prevents the brain from building tolerance at such a high rate, like many medications do today. Her research will also allow us to understand drug abuse better at the molecular level and the effects of dopamine at different regions of the brain, not to mention how the brain learns and expands plasticity.

Image references

http://medgadget.com/2009/01/european_unions_approves_deep_brain_stimulation_s ystems_for_parkinsons.html

http://www.bio12.com/ch17/IBNervous/Parkinson'sDopamine.jpg

http://biomed.brown.edu/Courses/BI108/BI108_2008_Groups/group07/PET_scan_Parkinson's_Disease.jpg

http://www.pennmedicine.org/encyclopedia/ency_images/encymulti/images/en/19515.jpg