By David N. Leff
Don't ever bad-mouth the snout of a pig (Sus scrofa). The gourmets among us have that porcine proboscis to thank for truffles - the uppermost-scale edible mushroom.
Truffles grow wild in the oak and chestnut forests of southern Europe. These pricey fungal delicacies lurk invisibly and rarely under the soil surrounding those telltale trees. It takes a female pig's special sense of smell to locate and root up a truffle because the odor the fungus emits reportedly mimics the pheromone wafted by an eager boar.
Now humankind can thank the pig's snout for a less down-to-earth capability: It could help neuroscientists to deal someday with accident-severed spinal cords, and diseases such as multiple sclerosis. It all goes back to that mammalian sense of smell.
"The olfactory neurons," observed Yale University experimental neurobiologist Karen Lankford, "die throughout your life. They live for only a couple of weeks, and new ones are continually being born in your nose. You may have had the experience if you have a cold," she continued, "that you don't smell anything for a week or so. This is because you've killed all your olfactory neurons - or most of them. And until new ones are born and grow from their axons into the brain's olfactory bulb, you won't smell anything. For the pig's nerve cells, it's roughly the same turnover."
At Yale University School of Medicine, in New Haven, Conn., Lankford is engaged in isolating and analyzing cells in the olfactory tract that coat neuronal axons with sheaths of myelin protein. These protect their ability to transmit electrophysiological messages.
It's The Myelin, Stupid - In A Pig's Snout
"There are three types of myelin-forming cells: Schwann cells, olfactory ensheathing cells (OECs) and oligondendrocytes," she explained. "As far as central nervous system repairs are concerned, most of the research emphasis has been on Schwann cells or OECs, because they are not attacked in autoimmune diseases such as multiple sclerosis. In MS, it's only the oligodendrocytes that are killed. It's not yet clear," she added, "whether Schwann cells or OECs are ultimately going to be a better type of donor cell for transplanting to treat trauma and disease.
"In a pig's snout," Lankford pointed out, "OECs themselves stay there all the time; they don't die off. The reason they're called OECs - olfactory ensheathing cells - is that in the olfactory system they don't normally form myelin. Transplant them someplace else - they're capable of forming myelin, though it's not a thing they usually do. Or if, in a laboratory animal, you injure the brain near the olfactory bulb, the OECs would crawl into the brain and form myelin.
"The reason there's been a lot of interest in porcine myelinating OECs for xenotransplants into human recipients is that olfactory nerves are the only nerves that are reborn throughout your life, and continually grow into the brain. It's thought that the cells that guide them into the olfactory bulb have unique properties that would make them useful for repairing spinal cord injuries, where axons are actually cut.
"One of the reasons that a transgenic pig transplant is so appealing for that application," Lankford pointed out, "is that unlike the peripheral nerves, olfactory nerves are hard to get at in a human." She and her colleagues are working with hard-to-harvest olfactory nerves from the snouts of transgenic pigs that lack the human gene for CD59. This encodes the protein that triggers hyperacute immune graft rejection in recipients from foreign donors.
The September issue of Nature Biotechnology carries a research article of which Lankford is a co-author. Its title: "Xenotransplantation of transgenic pig olfactory ensheathing cells [OEC] promotes axonal regeneration in rat spinal cord."
"We took a small piece of olfactory nerve," Lankford told BioWorld Today, "from the snout of a pig that was made transgenic for human proteins in a way designed to minimize immunorejection of cells from foreign tissue. We dissociated the OECs into individual cells and transplanted them into an area surrounding a partially severed spinal cord in rats.
"We didn't completely cut through the cord," she continued, "just snipped the top half with a pair of fine scissors. The only gap in the actual injury itself was a die-back of axons on either side for a couple of millimeters between the cut ends.
"My major role," she went on, "was preparing the cells for the transplantation, and analyzing some of the remyelination results later. We then looked at the functional properties of the axons after transplantation to see if the cells we transplanted were in fact there, alive, still expressing the same transgenic proteins, and making myelin."
The results? "Yes," she recounted, "the cells could make myelin. Yes, they could improve electroconduction. And yes, they still expressed the same protective proteins."
Yes, It Works In Folks, Too
A report in press in the journal Glia, Lankford related, described similar remyelination investigation involving human patients: "The Yale surgeons were actually taking OECs from brain surgery patients who had had parts of their olfactory bulb removed because of a tumor. They always tried to take out more of the area around the tumors so as not to miss any malignant cells. So they teased out the human olfactory ensheathing cells and transplanted them into the spinal cords of rats. And yes, human OECs proved able to do the same thing as our pig snout cells."
She and her group have been collaborating in an ongoing study with another group at Yale that is trying to develop a protocol for treating human multiple sclerosis patients. "Their lab," she observed, "is interested in seeing if transplanting some Schwann cells from the human nerve into an MS lesion might be a way of remyelinating those axons. We're working with them on the best way to develop a protocol we might be able to test with.
"The one thing we worry about a lot is that we don't really know what the environment is of the human MS nerve cells, or the type of injury that accident victims have that results in paralysis. It's our concern that while these cells might behave very well in the nice, clean, chemical-lesion model, there may be other things going on in trauma that would cause it to not work. At this point," Lankford concluded, "we're just trying to determine if we were to test this in people, what would be the best way to go about it."