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Photo John Schweitzer

RESEARCH

I spent 7 years doing anatomic pathology, neuropathology and post-doctoral fellowship at Washington University in St. Louis. My post-doctoral research was conducted in the laboratory of Dr. Eugene Johnson in the Department of Pharmacology. Gene was a hugely creative scientist and original thinker who made numerous important contributions in the field of the cell and molecular biology of trophic factors of the CNS. Working in his lab was the most fun and exciting period of my training. My project revolved around investigating whether an immunotoxin could be made and delivered to the Nerve Growth Factor (NGF) receptor bearing neurons located in a region of brain knows as the cholinergic basal forebrain (CBF). The rationale for producing this molecule could be summarized as the cholinergic hypothesis of Alzheimer’s disease (AD) and went something like this: The earliest neurochemical derangements that could be measured at the time were those of acetylcholine (ACh) in the CBF and the most profound loss of any neurochemical that could be measured was also that of ACh in the CBF. Furthermore, nearly all dementing illnesses (there are many besides AD, although AD is the cause of the vast majority of cases of dementia) show similar neurochemical changes in the CBF, and there is a large body of clinical and experimental literature that link lesions or drug effects in this area to deficits in learning and memory. The cholinergic hypothesis is now known to be overly simplistic. AD is clearly not a single neurochemical system disease as was hoped at the time. On the other hand, neurochemical derangement of the CBF is still considered quite relevant to deficits of learning and memory, and in fact the standard, mildly effective treatment that is available is thought to work precisely by increasing the effect of residual ACh in the CBF. I continued to work on this project when I took my first job at the Department of Pathology at the University of Tennessee, Memphis. It turns out that antibodies directed against the NGF receptor (in this case the p75 NGF receptor), when injected into the lateral ventricle of the rat brain, are readily internalized by the CBF neurons and no others. Therefore, anything attached to that antibody will potentially affect those neurons and no others.

Brannon Thomas went on to train in neurosurgery and acquire a Ph.D. in neuroscience in the laboratory of Dennis Steindler after working as a medical student in my lab, and Adam Book obtained a Ph.D. while working in my lab by making the next part of the project work. Although various toxins were tried, our major effort was directed at using a subunit of ricin toxin to selectively lesion the CBF neurons. (These are interesting toxins. A single molecule of the toxic or catalytic subunit, if introduced into the interior of a cell, is sufficient to kill the cell. The toxic subunit is an enzyme that rapidly and irreversibly disables a component of the protein synthetic apparatus. Once it has disable all or most such unites, the cell cannot live since it cannot synthesize any new protein.) Ron Wiley at Vanderbilt found that a similar toxin named saporin worked readily and the immunotoxin that resulted proved highly specific and lethal to the CBF neurons.

Vivek Singh was doing Ph.D. research in my laboratory when he wrote the paper above. He switched into pathology residency and in so doing went from being my graduate student to being one of my residents! (I was residency program director at the time.) He is practicing pediatric pathology in Kansas City.

A neurosurgeon named Alan Wyler led a comprehensive chronic epilepsy center at UT, Memphis, and he was very active in the area of neurosurgery for intractable seizures. This is a fascinating area, and the pathology of this condition is also very interesting. Together with my great colleague and friend, Dr. F. Curtis Dohan, Jr., we published some papers in this area.

In collaboration with Curt and the neurosurgery department led by J.T. Robertson, we also put together some proposals for the investigation of mechanisms of traumatic brain injury, another interesting and important field.

Upon my arrival at ETSU as Chair and Program Director of the residency program, my efforts became more collaborative. I’ve been fortunate to participate in some work done under the direction of Dr. David Williams in the Department of Surgery at the Quillen College of Medicine. Dave has a large laboratory operation that is doing highly original and important work on the cell and molecular biology of pattern recognition receptors (and downstream signaling of those receptors) in innate immunity. Dave got to that point by studying an immunomodulator derived from cell wall of fungi called glucan, and his research has extended to the cell and molecular biology of fungal wall products on Toll, dectin, and other receptors. Dr. Fang Hua conducted experiments as a post-doctoral fellow under Dr. Chuanfu Li in the Williams lab that show that the Toll-like receptor 4 (TLR4) mediates much of the damage to the CNS that occurs after a period of ischemia followed by reperfusion.

Dr. Hua has taken a position at Emory, where he will be continuing to study the effect of TLR2/TLR4 knockouts. We have also continued to investigate the signaling of the Toll receptors in a standard model of cerebral infarction (stroke):

Meanwhile we have found that a molecule called the scavenger receptor A (SR-A) interacts in this model in a quite complicated way with the various TLR receptors:

In addition, SR-A plays an important role in polymicrobial sepsis and we have written a review on this topic:

An exciting development has been the creation of the Center of Excellence for Inflammation, Infectious Disease and Immunity under the leadership of Dr. Williams and Dr. Moorman. The website for this effort is under construction and my be found at http://www.etsu.edu/com/ciidi/default.aspx

 

 

  John Schweitzer - schweitz -at- etsu.edu updated 10/12/2015