Treloar, et al. (2001): Mechanisms of axonal plasticity: lessons from the olfactory pathway

[Wise Young]

• Treloar HB, Bartolomei JC, Lipscomb BW and Greer CA (2001). Mechanisms of axonal plasticity: lessons from the olfactory pathway. Neuroscientist. 7 (1): 55-63. Summary: The olfactory pathway has emerged recently as an effective model for studying general principles of axon extension and regeneration. A variety of both trophic as well as repulsive molecules are found in the olfactory pathway and are being characterized for their roles in promoting the high capacity for plasticity and growth in olfactory receptor cell axons. In addition, olfactory ensheathing cells, which line the olfactory nerve, have been shown to promote axon extension not only in the olfactory pathway but also in the injured spinal cord. This review summarizes some of our current knowledge of these mechanisms and how they may function collectively to promote axon plasticity. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=11486344> Department of Neurosurgery, Section of Neurobiology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208082, New Haven, CT 06520-8082, USA.

[This message was edited by Wise Young on September 23, 2001 at 10:02 PM.]

[Wise Young]

The olfactory nerve is widely regarded as the only part of our central nervous system that can regenerate continuously in adult mammals. The olfactory nerves come from the olfactory bulb. This has long intrigued researchers and several have proposed that this ability of the nerve to regenerate is because of a very specialized cell in the nerve called the olfactory ensheathing glia (OEG) cell that live in the olfactory bulb and nerve. These OEG cells migrate rapidly alongside growing axons and also express the cell adhesion molecule L1 (which is also expressed by Schwann cells) that is believed to play a role in guiding axonal growth. Finally, OEG cells can ensheath axons, forming a kind of myelin around the axons. Over half a dozen laboratories have now reported that when they take OEG cells out of the olfactory bulb and transplant them into the spinal cord or the brain. Almudena Ramos Cuetos has shown that transplanted OEG will promote long distance regeneration and restore function in rats with transected spinal cords.

There is great interest in transplanting OEG into people. The problem is where to get the OEG from. One possible source is the person's own olfactory bulb. It is not easy to get to but it is possible. This is being considered by several groups, including the one in Spain and in Miami. Another possible source is to get OEG from aborted fetus (what they are doing in Russia). A third possibility is that they can be obtained from pig fetuses that have been genetically modified so that they are not immune-rejected when transplanted.

One of the problems of these experiments is the difficulty of isolating olfactory ensheathing glial cells. Several groups have been trying to do so. A second problem is getting consistent results from the transplantation. A third is that we don't really know what form of the cell is most conducive for stimulating regeneration. The cells differentiate into three forms in culture and it is not clear which of the forms is best for stimulating regeneration or remyelination.

Nevertheless, scientists are pressing ahead with the studies of OEG and planning clinical trials. This article is a review of the research by one of the original scientists who developed some of the methods of isolating olfactory ensheathing glia (Greer). He pioneered many of the early studies that described the morphology and behavior of these cells.

Wise.

[Carl R]

where is the olfactory bulb? What makes it difficult to obtain the cells?

[Wise Young]

The olfactory bulbs are situated at the base of the brain, under the frontal lobes. It is pretty deep and difficult to get to. However, several neurosurgeons have been practicing different exposures and it may be possible to get to the bulbs through an small cranial opening on the medial side of the orbit (of the eyes). They are developing these procedures in Miami and also in Madrid.

One group in England showed that it is possible to obtain olfactory ensheathing glial cells from the olfactory bulbs of people who have died. Also, several groups have been obtaining olfactory ensheating glial cells from the olfactory bulbs of aborted fetuses.

In the lab, we have been working on both adult and neonatal olfactory bulbs and getting the cells from those with some degree of success.

wise.

[Carl R]

when you say " developing ", what exactly are they doing now to develop the technique? Has it been tried on humans or rats? I am assuming, probably wrong, that the primary function of olfactory cells this for smell, is that correct? Do they have other functions as well?

[Sue Pendleton]

Medial side of the orbit? That's the oustide of the eye socket towards the temple and still under the eyebrow bridge, right? Geez, I already have a small scar there on my left eye. Anyone need a human subject for a one side only removal and insertion to where the cells are needed? I'd really prefer not flying to Russia if I don't have to especially in winter.

[Chris Chappell]

We'll wear big furry Russian hats. If you're game to go to Russia so am I. But is it the best place / alternative?

Wise, you mentioned "planning clinical trials". Once setup what do you think the trial would entail in terms of procedure? Goals? Anticipated / projected outcome?

And the inevitable question of when do you think these trials may take place? Is any facility domestic or abroad ahead of another?

Tell me when, where and why to go and I'll be on the next junket to wherever. I'm ready to be a proverbial guinea pig because I believe in the method behind the madness. I can guess that your answer will be to wait but I believe the science is here to achieve functional recovery and like Edison and the light bulb we need to do a lot more trial and error to perfect it. This will require risk and offer opportunity. http://sci.rutgers.edu/forum/images/smilies/tongue.gif

[Sue Pendleton]

I'm game, Chris. Maybe we could go back when Dmitriy heads back? He'd make a good guide and translator. My Russian consists of getting beer, vodka, telling people not to move or I'll shoot and a few cuss words. Oh, and thanks and you're welcome. I do know health care is cheaper over there even for foreigners but insurance will not pay. Well, maybe. Mine is supposed to be good all over the world. Think I see a poll I need to post.

I can't see why we aren't trying this here in the US yet either. To be quite honest I was taken a back when I read what Wise said about journals not caring if the animals walk just how they did it and and was it due to regeneration or what. Well I don't care what journals want. Those are just pieces of paper that keep some publisher types employed and keep other scientists too busy reading and reviewing prepublished articles to do things that help humans. I'm living and breathing at least for a few more months. What kind of science is that if the only outcome is why and how and not that it does? If we used that kind of logic on the Manhatten Project we would have had to fight Japan on their territory. Two thirds of their scientists weren't 100% sure that the nuclear reaction would stop at the bomb site and not go on to fire up the entire atmosphere of Earth.

We need a new way to judge scientists for tenure and promotion than just being published on how to regenerate the nerve cells of Zebrafish. Who cares how a Zebrafish regenerates? An ocenaographer, maybe? Certainly no one currently paralyzed. I mean it's a fish! How about grading papers also by their relevance to human health in the appropriate science areas? Grants are often judged on this along with other outcomes so why not the papers that come from the work?

I've often felt we could cut the military budget by about 10% easily by hiring a couple privates to look through the wish lists from the Pentagon. Maybe we need ill, disabled or dying people on more of these boards giving grant money out. I don't think one board set up by the states with research laws does not have someone with a SCI on them. Maybe NIH needs a wake up call.

[John B. Stevens]

TO SUE PENDLETON

THANK YOU FOR YOUR REPLY. I ACCIDENTLY SENT THIS ANSWER TO SHARON-ANDERSON. I COULD NOT FIND YOUR DIRECT E-MAIL SO I HOPE YOU SEE THIS.

MY STROKE BEGAN AS LOWER BACK PAIN OUT OF THE BLUE, I DID NOT HAVE AN ACCIDENT, MY LOWER BACK JUST STARTED HURTING AND THE PAIN RADIATED TO MY WAIST, HIPS, AND THEN DOWN MY LEGS. WITHIN AN HOUR, I COULD NOT WALK AND THE PAIN WAS GONE. I CAN NOT TELL THE DIFFERENCE IN HOT OR COLD BELOW MY RIBS. MY RIGHT LEG HAS MORE FEELING THAN MY LEFT AND I CAN FEEL TOUCH IN MY RIGHT LEG BUT NOT MY LEFT. MY RIGHT LEG HAS SPASMS THAT GO UP TO MY RIBS BUT NO PAIN. I ALSO NOTICE THE MUSCLE TIGHTENING ON THE INSIDE OF MY RIGHT THIGH. I HAVE THE TINGLING, PINS/NEEDLES EFFECT IN MY BUTTOCKS AND BOTH LEGS BUT MORE PREDOMINANT IN MY RIGHT LEG. I HAVE NOTICED MORE TINGLING AND WHAT SEEMS TO BE SPASMS IN MY LEFT LEG AND FOOT BUT ONLY TO A SLIGHT DEGREE. MY DOCTOR DID NOT MENTION COMPLETE OR INCOMPLETE BUT I ASSUME INCOMPLETE SINCE THERE WAS NO ACTUAL ACCIDENT/OPERATION OR ANYTHING LIKE THAT. POSTERIOR? I DON'T KNOW ABOUT THAT BUT WILL FIND OUT FROM MY DOCTOR. I DON'T THINK I WAS GIVEN ANY MEDS IN THE EMERGENCY ROOM AND DID NOT HAVE AN MRI UNTIL ABOUT 8 HOURS AFTER MY FIRST PAINS. I HAVE BED SORES ON BOTH MY HEELS THAT WERE ALMOST HEALED WHEN MEDICAID DECIDED I DID NOT NEED THE REGRANEX ANYMORE. WE USED ANOTHER MED AND IT MAY HAVE DONE MORE DAMAGE AND SET ME BACK A FEW MONTHS. THEY NOW ARE PROVIDING IT FOR ME AT $450.00 PER TUBE. I DO HAVE A LOT OF BURNING/TINGLING IN BOTH HEELS. I WAS TAKING NEURONTIN FOR THAT BUT NOW TAKE LORCET ONLY WHEN I NEED IT AND AT BED TIME AND IT SEEMS TO WORK BETTER. I PRETTY MUCH LIMIT THE LORCET TO TWO A DAY.
THANK YOU FOR YOUR CONCERN AND I WILL GET MY RECORDS AND ANSWERS ON SOME OF YOUR QUESTIONS.
WISE YOUNG SENT ME AN E-MAIL I AM GOING TO REALLY HAVE TO STUDY TO GET THE ANSWERS TO HIS QUESTIONS.

I HOPE I WILL BE ABLE TO WALK ONE DAY SOON BUT IF NOT, I WILL JUST DO THE BEST I CAN.

THANKS AGAIN FOR YOUR CONCERN AND REPLY,

JOHN B. STEVENS
jbstevens57@aol.com

John. B. Stevens

[Wise Young]

John Stevens, can I suggest that you do not type your posts in all capitals? On internet, the use of all capitals is similar to SHOUTING and it is considered by many people to be rude. Thanks. Wise.

[Chris Chappell]

You're ahead of me in the russian dialog department. I can barely say stolichnaya. Dmitry should come along. When does he go back?

I completely agree with your zebrafish and manhattan project analogies. That's why my renewed focus is on finding the right doctor or neurologist who, domestic or abroad, armed with enough knowledge, and intestinal fortitude to pull the trigger will want candidates to undergo a procedure where the goal is complete functional recovery in terms of nerve regeneration, reconnection. Leave the rehab up to me.

It seems that many doctors, including Wise, want the procedure to be right before they aggressively experiment. It's obviously sensible but also slow and obtuse. My belief is that we have to aggressively experiment ON HUMANS to get it right. Sharp, determined, focused and logical experiments. The FDA and the attorneys would have a field day I know but there has got to be a way in which as a candidate you can absolutely absolve anyone from legal / medical retribution.

Bottom line is just give me a 50/50 chance to get out of this situation and I'll decide whether its worth it or not.

[Wise Young]

Chris,

The details are really important and I am just as frustrated by everybody by the slow pace of some of the therapies. The goal is to find a therapy that works and that can be made available to everybody with a well-run clinical trial. The problem with going "aggressively" in humans is that it just takes one death or a few cases of something not working for everybody to abandon the therapy. Can you imagine what would happen if a surgeon goes ahead and takes out an olfactory bulb and then fails to isolate viable olfactory bulb cells from the tissue. Would you want the surgeon to come back and say "whoops, I am sorry"...

While there has been much interest and discussion about going to Russia for transplantation of fetal stem cells and olfactory ensheathing glia, the reason that it is not happening in the United States is not the surgeons or the FDA. It is the American people who opposes this kind of therapy. No insurance company would pay for such a therapy. The National Institutes of Health is still not allowed to fund such a trial... No company would be interested in funding such a trial.

It is important that we identify the real causes of the slow progress and correct them.

Wise.