[music plays] [narrator:] one ofthe most intriguing uses of stem cells can be foundin the field of regeneration. whether the goal is toregenerate damaged heart or nerve cells or toregenerate an entire limb, a similar process must occur. a damaged tissue mustrewind development, calling on cells that canreverse their differentiation
or rallying reservoirsof stem cells that can generate bothdifferentiated cells and more stem cells. humans can regeneratecertain parts of the body. wound healing is a poorcousin of regeneration. but the humanliver, for example, can regenerate an entirepiece if it has been lost through damage or surgery. other vertebrates are moreproficient than mammals
at regeneration. some lizards and salamandersregenerate lost tails. and salamanders canregenerate entire limbs. however, the organism withone of the most incredible abilities to regenerateis the planarian. this worm's regenerativecapabilities have been known forhundreds of years. and today modernmolecular-biology techniques are turning this old favoriteinto a powerful new model
for understanding thepotential of stem cells. planarians arefree-living flatworms and are related toparasitic flatworms, like the liver flukeand the tapeworm. they are found throughout theworld in wet environments. they range in size from3 to 12 millimeters and are scavengers,feeding on the decaying remains of animals and plants. dr. alejandro sanchezalvarado, an hhmi investigator
at the university ofutah, describes some of the planarians' physiology. [alvarado:]planarians derive their name from the fact thatthey're fairly flat. "planum" means "flat,"and hence "planarians." and the reason whythey're interesting is because these are perhaps thesimplest organisms that display a centralized nervous system. so the central nervoussystem is composed
of two lobes that looklike a horseshoe shape, around this area right here. and those two are connectedto ventral cords that send projectionsall the way down to the very tip of the animal. and this is howthe brain basically controls the motion andmusculature of these animals. this dark grey area right hereis part of the gastrovascular system.
this little thing righthere is a muscular pharynx which actually comes outfrom the ventral surface-- from the belly ofthe animal-- out and is used to impale--literally impale-- food and suck it back in. now planarians arefunny, because they don't have a mouth. so they only have a singleopening to their body, and it's through this pharynx.
so the food entersthrough the pharynx. it is digested. and whatever is notdigested and is not dumped into therest of the animal comes back out throughthe same pharynx. so it's an organ thatserves two functions. these two cartoon-lookingcockeyes right here actually are the photoreceptorsof these planarians, or also known as "eyespots."
and what these eyespotscan do is detect light. and planarians don't like light. they're phototacticallynegative. so whenever they seelight, they'll just run away from the light,and it'll hide somewhere. and this is perhaps theprototypic darwinian eye, which consists of alight-sensing organ and a pigment-cup organthat allows for the light to be handled by the organism.
[narrator:] butwhat makes a planarian so exceptional atregeneration is its ability to rapidly grow even very smallbody pieces into completely formed worms. unlike the cellsof most animals, most of the cells inthe planarian's body can act like stem cells. if you cut a planarian in halfbetween its head and tail, the tail half grows a head andthe head half grows a tail.
if you cut it lengthwise,the two halves grow new second halves. you can even bisect justthe head, between the two eye-like photoreceptors,and you will end up with a worm with two heads. this process can be takento incredible extremes. dr. sanchez alvarado describesthe planarian's ability to regenerate. [alvarado:]so you can take a planarian
and slice it intoeight fragments. and each fragment will go on andregenerate a complete animal. that would be like sayingthat you can cut your ear off and then a new you willarise from that ear. well, planarian can do that. we can't, butplanarians can do that. morgan, in 1898,demonstrated that you can take a fragmentthat's 1/279th the size of the original animal.
and the tiny little fragmentfrom the flank of the animal will be capable of restoringall of the missing parts and produce a complete andproperly shaped organism. and it does this inabout a week or so. and so that just givesyou an idea of how plastic these animals are. [narrator:]thomas hunt morgan investigated the planarians'regenerative powers at the turn of the 20th century.
even before morgan,charles darwin wrote about planarians hefound during his voyage on the beagle, describingtheir abilities and illustrating their anatomy. what new informationhas modern-day biology been able to uncoverabout planarian stem cells and regeneration? and what do thesefindings tell us about the human capacityfor regeneration?
at the university of utah,the sanchez alvarado lab is using today'smolecular-biology tools to uncover the secretsbehind the planarians' remarkable abilities. they use a particular typeof planarian-- schmidtea mediterranea-- intheir research. otto guedelhoefer, a graduatestudent in the sanchez alvarado lab, explains the advantagesof using planarians to study stem cells.
[guedelhoefer:] but i didn'tfeel like the mammalian system is ready to tell us a lot. i felt like a lot ofthe basic knowledge that we need to know in orderto ask the right questions about stem cellsneeded to be discovered in a much simpler organism. so, although the mouse workis very, very interesting, i thought studying it ina much simpler organism would be much more interesting.
and that's how i gotturned on to studying stem cell biology in planaria. [narrator:] experimentsusing rna interference, or rnai, were designed toidentify the genes involved in the planarians' neoblasts--the stem-cell-like cells that migrate to areas of damageand allow the worm to regrow the missing parts of its body. the rnai experimentsidentified 240 genes involved in a planarian'sregeneration, including
one coding for aprotein called smedwi that is similar to proteins foundin fruit-fly stem cells and during the process ofhuman sperm maturation. [alvarado:] this molecule-- smedwi-- receivedits name because it's a homolog of a moleculethat was discovered in drosophila called piwi. and piwi is a molecule thatwas identified in drosophila as being responsible for themaintenance of the stem cells
in the gonads of the female fly. we were expectingpiwi to actually play a role in regulating themaintenance of the stem cells that are found in thebody plan of planarians. and so the original phenotype--the defect that we uncovered by eliminating this geneusing double-stranded rna said that that was the case. because the animalslooked a lot like what irradiated animals look like.
and irradiated animalsbasically have no stem cells. because the stem cellsare the only cells that divide in planarians. so you subject them tolarge doses of irradiation, like you would do forcancer, for example. all the dividingcells are eliminated. and there's no stem cells toproduce new daughter cells to go in and replace these dyingcells, and the animal dies. and it dies in avery specific way.
the head begins toresorb back, and the body begins to assumea ventral curling. so the animal now looksalmost like a taco shell. when we silencepiwi with rnai, we get exactly the same phenotype. a regression of the headand this curling phenotype. so we thought, aha! when we look at theseanimals in detail, all those stem cellsare going to be gone.
because we're essentiallygetting the same defect. but we were surprised, becausewhen we went and looked at these animals we realizedthat the stem cells were there. they were happy. the stem cells were actuallyresponding to tissue turnover. so they would producingdivision progeny. and so the messagethere was to us that piwi not only had afunction in the maintenance of stem cells, but it alsohad a function in regulating
the function of daughter cells. so you're causing a defectearly on in the life history, even before that cell is born,that when the cell that is now born, it's supposed to go onand differentiate: it cannot. and then it fails, andit undergoes apoptosis, most likely, and then it dies. so the lesson is actuallyquite profound for us, because it tells us that thismolecule piwi is actually doing something to thegenome of the stem cell that
will determine whether ornot the daughter cell will be functional. [narrator:] buthow much of this knowledge will be relevant tohuman stem cells? [guedelhoefer:]i think the main thing that could be applied to humanand vertebrate biology, based on what we're learningin the planaria right now, is identification of genes. so by identifyingthese genes that
are involved in planariaregeneration, hopefully we can understand theirfunction in humans. if these are genes thatare promoting regeneration in planaria, it may be possiblesomewhere far down the line to turn these geneson pharmacologically. and they may have someeffect in vertebrates. [alvarado:]multicellularity's been around for about 600 million years. so the history of life onthis planet is unicellular.
it's just all single cells. so it took three andhalf billion years. only 600 million years ago,multicellularity emerged. and one of the fundamentalattributes, i think, of multicellularity is themaintenance or segregation of the germ lineinto stem cells-- to repair tissue, whichwe damage all the time. even drosophilahas now stem cells in its gut, which is absolutelyrequired to give nutrition
to the stem cellsin the gonads, such that the animal can reproduce. so i think all of theseprocesses, at some level, are going to be conserved. by studying planarians, we mightbe able to inform that biology and, by extension, understandour own biology a little bit better than we do today.
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