Staying Young: Regeneration in Planarians

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00:00:06.13 So, hello, my name is Alejandro Sanchez Alvarado.
00:00:09.19 I am an investigator with the Stowers Institute for Medical Research,
00:00:12.21 as well as the Howard Hughes Medical Institute.
00:00:15.13 Today we're going to be talking about this cryptic title,
00:00:18.23 called "Dying young as late in life as possible:
00:00:21.11 tissue homeostasis, regeneration and stem cells."
00:00:24.11 And why dying young as late in life as possible?
00:00:27.07 This actually underscores a very fundamental principle of life
00:00:30.25 that is broadly manifested in every multicellular organism,
00:00:34.29 irrespective of whether they're plants or they're animals,
00:00:37.13 and you can find it in the most common places,
00:00:39.21 as well as in the most inhospitable places.
00:00:41.24 So, I wanted to take an extreme and take you to a very inhospitable place,
00:00:45.12 that is in South America, this is a map of the globe of earth, of planet earth,
00:00:52.07 where we live, let's say we're going to take a trip from North America
00:00:54.19 down to South America and what you're going to see here,
00:00:57.05 is that we're going to go to the northern part of Chile,
00:00:59.21 between the borders of Chile and Peru, there's this tremendous desert
00:01:05.09 that spans south and north of the coast of Chile,
00:01:08.12 called the Atacama Desert. And the reason why I want to take you here
00:01:12.11 is because there is a very interesting manifestation of life
00:01:15.16 that inhabits this incredibly desolate plains of landscape that do something really, really remarkable.
00:01:24.06 And this plant's right here.
00:01:25.29 It's scientific name is Azorefla compacta
00:01:28.05 and you're looking at one such specimen,
00:01:30.07 and what I'm going to do is that underneath this picture,
00:01:33.00 I'm going to draw a timeline, and there it is.
00:01:36.04 Starting from time 0, and going all the way to, you know, where I'm standing essentially.
00:01:41.11 And what Iâ€™m going to do with this is illustrate
00:01:43.13 something that's truly remarkable about multicellular life.
00:01:46.24 So, I want to start by saying that when the first extra solar planet was discovered in 1988,
00:01:52.01 this plant was happily growing and existing on the plains of this inhospitable place
00:01:57.14 called the Atacama Desert.
00:01:58.23 Now that would make the plant approximately, you know, 30 years old or so. Alright.
00:02:03.20 So, you can go back a little bit more in history
00:02:06.25 and go to the first time that an atomic bomb was detonated on the planet.
00:02:10.20 This was in 1945.
00:02:12.13 And botanists estimate that that plant was actually living there just fine.
00:02:15.28 You can go further. You can go all the way back to 1842,
00:02:19.20 which is about the first time that Darwin was beginning to write down and think about his theory of evolution,
00:02:25.21 and this plant is believed to have been growing and living already
00:02:29.29 out on the Atacama Desert.
00:02:32.16 That makes the plant already, you know, close to 150 to 200 years old.
00:02:36.26 Now that's pretty remarkable for a single multicellular organism,
00:02:40.26 but it gets even more intriguing, because if you go even further,
00:02:44.09 all the way back to 1609, when Galileo first aimed a telescope at the moon,
00:02:48.26 it's believed that this plant was still growing on the Atacama Desert.
00:02:52.13 That's already 400, 420 years or so.
00:02:55.00 So, that makes it already pretty astonishing. But you can go even further than that.
00:03:00.17 You can go all the way back to 1347, the continent of America had not been discovered,
00:03:05.20 the Black Plague was decimating most European countries,
00:03:09.01 and this plant was growing as if nothing was happening in the rest of the world.
00:03:12.16 1347, this plant was already living for several centuries,
00:03:16.19 it was a several-century old plant. And you can go all the way back
00:03:20.21 to the Summa Theologica, which was written by Thomas Aquinas
00:03:23.24 in 1273, and who might be somewhat responsible for most of these events
00:03:28.09 that happened a posteriori, later on, but this plant is estimated to have been growing
00:03:34.20 on these plains of the Atacama Desert. In fact, and I'm going to stop,
00:03:38.18 because I don't want to go all the way back, but you can actually sum up
00:03:41.12 the rise and fall of the Roman Empire and the plant was still growing on the Atacama Desert.
00:03:46.07 So, this is even before there is civilization, essentially,
00:03:50.06 organized society, this plant was growing, you know, completely impervious,
00:03:54.28 completely, you know, ignorant of everything that was going on around it.
00:03:59.22 The key thing here is that this plant is estimated to be at least 3,000 years old.
00:04:05.05 That is an incredible astonishment, incredible and astonishing phenomenon
00:04:11.15 that is manifested by plants. But it's not just plants, it's also a lot of other organisms.
00:04:15.23 So, why can this plant live for 3,000 years?
00:04:18.25 So, the fundamental reason why it can live for 3,000 years is because there is a key principle
00:04:24.04 in its biology that allows it to survive and thrive essentially impervious
00:04:29.17 to the passage of time. If you look closer at this plant, it looks like a series of rosettes,
00:04:35.12 you can see those all floating around here,
00:04:37.05 they all seem to be organized in a series of Fibonacci series,
00:04:40.11 so I'm going to increase that, so you can take a look at it.
00:04:43.16 So, you can see these really nice little rosettes, essentially organized all around each other.
00:04:48.10 In the center of each of these rosettes lies a very interesting population
00:04:52.13 of cells in a structure called the apical meristem.
00:04:55.24 And this apical meristem is populated by stem cells,
00:04:58.29 which we're going to be talking about for the next 20 minutes or so.
00:05:02.04 These stem cells are responsible for the production of every single cell type
00:05:06.03 that is found in this particular plant.
00:05:08.04 The colors, the different functions for breathing, for respiration, for capturing sunlight,
00:05:14.16 roots, et cetera, et cetera.
00:05:16.06 All of those actually come from stem cells that are organized in these meristems in these plants.
00:05:21.10 Now, you and I clearly don't live for 3,000 years.
00:05:24.09 I don't even know if I want to live for 3,000 years if I think about it.
00:05:27.28 But we do some really remarkable things that are also equally astonishing.
00:05:33.11 And I'll give an example.
00:05:34.16 So, here's Leda, this is painted by Leonardo da Vinci,
00:05:38.25 I like these drawings that he was doing of the human body, and human anatomy at the time,
00:05:42.24 but what I want to tell you about this is that
00:05:44.21 it is being estimated that in a single day, you and I
00:05:48.17 will replace, will lose and replace, anywhere between 50 to 70 billion cells.
00:05:53.15 Now, these are American billions, these are not metric billions,
00:05:56.22 because if you're aware, metric billions we would just disappear,
00:05:59.14 but 50 to 70 billion cells.
00:06:01.27 Now, if you do the math, if this is happening every single day,
00:06:04.14 and you add how many cells you lose every single day for 365 days,
00:06:09.01 what happens is that in a year, each and every one of us would have produced,
00:06:13.07 and at the same time, eliminated, a mass of cells that is equal to our entire body weight.
00:06:18.13 Now, think about it for a second. I woke up this morning,
00:06:21.06 you know, getting ready to come here today, I give you this presentation,
00:06:24.14 and I recognize myself in the mirror, even though between today and yesterday,
00:06:28.20 I lost 50 to 70 billion cells.
00:06:30.18 If this loss of cells was completely uncontrolled,
00:06:34.13 there is absolutely no way that you and I grow to live for 80 years if we're lucky,
00:06:39.06 and maybe beyond that.
00:06:40.13 But that is a really remarkable thing to think about.
00:06:45.00 That we, every day, are losing this many cells, and still retain our external appearance
00:06:49.17 and our form and function. That our parents can recognize us,
00:06:52.18 that we can recognize our children, is truly remarkable.
00:06:56.04 And the reason why this happens is because there's a process
00:06:59.05 that allows us to grow and to thrive through a long period of time.
00:07:05.27 And this process of longevity, which is underpinned by a series of mechanisms,
00:07:10.05 which we're going to discuss in the next few slides.
00:07:12.04 So, what I would like to discuss for the next few slides is the following:
00:07:15.12 how is the long-term maintenance and repair of our bodies maintained?
00:07:19.20 How is this done? How could it be that from a single cell after fertilization,
00:07:23.05 we can grow to, you know, be human beings and after birth, continue to grow,
00:07:27.15 and after we finish all our growth, we continue to live for several decades
00:07:31.08 after that. How do we maintain this anatomy, how do we maintain our form and function,
00:07:36.01 without dropping dead like flies?
00:07:37.25 And this should be happening, but it's not happening, it's an incredibly robust and stable system.
00:07:41.18 So, I would like to cover four topics.
00:07:44.01 First, is the cellular agent that appears to be mostly responsible for the maintenance of this form and function,
00:07:49.16 throughout life, which are called stem cells.
00:07:51.06 And if you have been spending the last ten years playing Minecraft,
00:07:54.21 you would not know what stem cells are,
00:07:56.00 so I'm sure you've heard about stem cells, may or may not be.
00:07:59.10 Secondly, you know, what is tissue homeostasis,
00:08:01.06 which is a fundamental process that allows us to retain this form and function, we'll talk about that.
00:08:06.10 Third and penultimate topic I want to discuss is regeneration,
00:08:10.17 and there's a difference between tissue homeostasis and regeneration,
00:08:13.06 and we'll discuss that as well.
00:08:14.24 And then finally, how can we study these very complex processes,
00:08:19.02 the stem cell function,
00:08:20.07 the functions that allow the stem cells to produce all of these other situations,
00:08:24.20 tissue homeostasis and regeneration problem.
00:08:27.08 So, let's start with what are stem cells, which is topic number one.
00:08:31.21 So, stem cells are famous because they are known to the press
00:08:35.27 and they have been discussed everywhere and everyone is thinking about them.
00:08:39.05 Because they promise to repair and fix a lot of human maladies,
00:08:44.09 particular diseases of congenital origin,
00:08:47.17 meaning things that you inherited from your parents, or your family,
00:08:50.09 or, you know, just accidental insults from the environment, injuries, and those kinds of things.
00:08:54.28 So, here's a picture of a hematopoietic stem cell.
00:08:58.13 And you can see this stem cell has essentially two properties
00:09:01.29 which are fundamental and are shared by all stem cells.
00:09:04.12 Number one: these are cells that produce progeny that are like themselves,
00:09:08.29 and also unlike themselves.
00:09:11.25 So, for example, when they copy themselves, these process is referred to as self-renewal.
00:09:16.15 So, the cell divides, one of the cells will actually go and make itself again,
00:09:21.15 and this is called self-renewal,
00:09:23.21 and then the second step is what happens to the other daughter cell.
00:09:27.27 The other daughter cell will actually go on and not become a stem cell,
00:09:31.19 but will go on to differentiate. Here's an example of the types of differentiated cells
00:09:35.17 that these stem cells would make.
00:09:36.29 These are blood cells. So, our entire blood system
00:09:40.09 is fueled, completely fueled, by this type of biology. Stem cells that reside
00:09:47.08 in the, inside of bones, in the bone marrow of our bones,
00:09:51.02 and these stem cells will actually go and do this self-renewal that I'm showing you here,
00:09:54.22 and produce these various cell types that you see right here.
00:09:57.25 There's lymphocytes, there's polymorphonuclear lymphocytes, et cetera, et cetera.
00:10:01.29 So, there's a broad and wide diversity of cell types which keep us alive
00:10:05.14 and defends our bodies against all kinds of insults from the environment.
00:10:09.07 So, that's what defines a stem cell, it's self-renewal and it can produce cells
00:10:14.12 that are different from itself. So, where are the stem cells?
00:10:18.10 Well, stem cells in the human body are in many places.
00:10:20.20 And in fact, I believe that not all stem cells have been discovered residing in our bodies.
00:10:25.23 For example, the list just keeps on growing and growing.
00:10:27.18 They've been found in the central nervous system, or the CNS,
00:10:30.22 they are in an area of the brain called the subventricular zone,
00:10:33.11 which is inside of the brain separated by the corpus callosum.
00:10:37.23 They have also been found in the hippocampus, they were found in the olfactory system,
00:10:42.27 this is one of the few neurons that actually regenerates after, you know,
00:10:45.12 they're damaged by a very strong smell, they will actually grow back.
00:10:48.20 They are found in the hematopoietic system, that's the blood system we just discussed,
00:10:52.03 in the skin, every time you go to the beach, or to the pool,
00:10:54.21 and you get sunburned, you lose the skin, it grows back. That's all driven by stem cells.
00:10:59.02 Muscle- if you exercise, which I think you should be doing,
00:11:02.19 then what happens is that those muscle fibers will die,
00:11:05.28 but there are resident stem cells that will actually go on to reproduce tissues.
00:11:09.02 The digestive system and many more.
00:11:11.21 So, these just keep on appearing, when people look and look and look,
00:11:17.00 they keep on finding more and more stem cells, and it's not entirely clear
00:11:20.01 where they all come from through development, and it's a very active area of investigation.
00:11:26.14 So, that's what stem cells are, and where they are, and what they are likely doing
00:11:30.12 to maintain our biology. But, the process by which they do this
00:11:36.14 is referred to as tissue homeostasis.
00:11:38.21 And tissue homeostasis is essentially pictured in this slide.
00:11:41.25 So, you have a stem cell, which actually undergoes self-renewal,
00:11:45.20 which is this little arrow you're seeing right here,
00:11:47.15 that cell will actually now produce a daughter cell. Now this daughter cell
00:11:51.23 can actually do one of two things. It can amplify itself, which you can see down here,
00:11:55.25 so it makes more depending on how many more cells are needed
00:11:58.04 by the tissue, or it can actually go from this individual all the way into the tissue
00:12:03.05 in which it's going to integrate itself. So, this is a good example, an example of
00:12:08.00 tissue homeostasis is given by when you eat a very, very spicy meal.
00:12:12.24 Say you go to an Indian restaurant and you ask for extra hot.
00:12:15.23 Ok, well the extra hot is actually going to kill a lot of the cells that line your gastrointestinal tract
00:12:22.04 and this is, you know, the sensation that you get.
00:12:24.10 Those cells are killed by this compound called capsasin, which is found in red hot peppers.
00:12:28.12 And what happens is when the cells die,
00:12:30.14 somehow, through mechanisms we don't quite understand,
00:12:33.07 they send signals to these resident stem cells and tell the cell,
00:12:37.09 hey, we just a differentiated cell, we need more. Because if we keep on losing cells,
00:12:42.02 we'll lose our integrity, and you'll get more than a stomachache,
00:12:45.21 you'll get an ulcer. So, what happens is that the cell will go on,
00:12:48.19 intercalate in this tissue, go back into the tissue, and then differentiate into an epithelial cell,
00:12:54.01 and this goes on over and over.
00:12:56.03 So, tissue homeostasis refers to a process by which our organs
00:12:59.10 can keep an optimal state of being.
00:13:02.03 These situations are required by physiological changes.
00:13:05.24 So, tissue homeostasis is essentially the process by which you are repairing physiological wear and tear,
00:13:13.10 whether it's the lining of your gut, or whether it's in the muscle,
00:13:15.24 or whether it's in your skin, this is just normal wear and tear
00:13:18.23 and you don't really run out of these tissues for a long time,
00:13:22.05 because you have these stem cells making the tissue anew, all the time.
00:13:26.07 For example, the lining of your gut, just to give you an idea of how immense this process is,
00:13:30.29 the lining of your gut, if you were to spread it out on a thin surface,
00:13:34.21 a single cell layer thick, ok, that will cover a surface area of a tennis court.
00:13:39.14 That is being replaced in your body essentially every five days.
00:13:43.00 This is a remarkable thing that your body is doing every single day,
00:13:46.17 there's a constant replacement of these cells.
00:13:49.02 And so, and the fact is that when it happens, it doesn't happen in a disorganized fashion,
00:13:52.27 it happens in an incredibly organized and choreographed fashion
00:13:56.08 such that the structure of the gut is retained,
00:13:58.25 such that the function of the gut is retained, and these are processes
00:14:02.02 that are still quite mysterious to us scientists and is, again, a very active
00:14:06.18 area of research. Ok. So, that is essentially how the process of tissue homeostasis
00:14:13.24 is conceived of by scientists.
00:14:17.13 Well, how can we measure this?
00:14:18.13 Is it really happening? So, I'm going to give you a really good example
00:14:21.07 of a manuscript that came out in 2005 by Spalding et. al.,
00:14:24.17 that actually took advantage of these atomic explosions
00:14:27.09 that I told you about.
00:14:28.22 So, what happens if you look at this graph is that from the beginning of history,
00:14:32.00 dating all the way back to 0 B.C., all the way back to the 2000's or so,
00:14:37.14 the amount of carbon-14 that was in the atmosphere is very, very low.
00:14:40.28 You can't see anything before the first atomic explosion, right around here,
00:14:45.08 you see this huge peak going up because these were atmospheric explosions.
00:14:48.22 In the Atolls of the Pacific, in Arizona, and in Mexico, these things were being blown up
00:14:54.12 to test, you know, how powerful these reactions were.
00:14:58.09 So, what the scientists did was the following:
00:15:00.01 they reasoned that since DNA is made out of carbon,
00:15:03.08 because we're carbon beings, we could actually measure
00:15:05.23 this carbon-14 in individuals that were born somewhere around this period.
00:15:09.13 And then see how quickly this carbon-14 disappears from their tissues.
00:15:13.23 So, they did this first with plants. Ok, so just to show you this is really conserved
00:15:17.13 for all multicellular organisms. So, here are the rings of a plant,
00:15:21.16 you can see that, this is how we actually measure, you know, the age of these plants.
00:15:25.03 So, each ring represents a particular year, or a particular decade in this case,
00:15:28.14 and what they did essentially is they went into each of these rings and collected a little bit of sample,
00:15:33.00 bloop, bloop, bloop, put them into a tube, and then processed them
00:15:37.09 to detect the amount, or the concentration, of carbon-14
00:15:40.20 that these tree trunks had.
00:15:42.08 And again, if you follow, down here,
00:15:44.23 before the first detonation of the atomic bomb,
00:15:47.04 the carbon-14 is very low. But afterwards, it just goes up.
00:15:50.15 Now, it goes all the way to the top and then it declines. Why do you think it declined?
00:15:54.21 It declines because treaties were signed to prevent explosions
00:15:58.20 of atomic weapons in the atmosphere. Also, the explosions that were tested
00:16:02.13 from that point on were underground.
00:16:04.17 So, the carbon-14 actually decays through time,
00:16:06.17 and it decays through time simply because the tissues are turning over.
00:16:10.17 So, you can see that, when we go back to the 2000's or so,
00:16:13.09 right over here, what you see essentially is that the carbon-14 has dropped.
00:16:18.22 So, now they reasoned, well, this is true for trees, how about us humans?
00:16:21.22 So, this is what they did. They went back and they looked at populations of humans
00:16:25.25 that were born somewhere in the 1950's, 1960's,
00:16:28.10 that would be somebody like me,
00:16:30.23 and then they measure what the amounts of carbon-14 were in these individuals through time.
00:16:34.15 So, if we have tissues that are turning over very, very quickly,
00:16:36.28 the amount of carbon-14 that you will find in those tissues
00:16:39.13 will be very low. But if the tissue is static, and it's not changing very much,
00:16:44.05 the amount of carbon-14 will be very high. So, here's a collection of what they found.
00:16:48.07 So, here is "Google man", this guy you can find in Google,
00:16:51.15 I don't even know if people know that this picture is all over the internet,
00:16:56.11 but we use it for teaching anatomy.
00:16:58.19 And so here is the situation.
00:17:00.11 Cells of our body turn out to turn over at very different rates.
00:17:04.28 This is still more complicated.
00:17:06.22 So, for example, in the brain, the cells appear to be turning over in years.
00:17:10.16 It's not in days, it's not in hours, it's in years.
00:17:13.11 That kind of makes sense, I cannot imagine, you know, keeping the same personality
00:17:16.19 if all of my neurons were changing daily.
00:17:19.07 Just think about that for a minute.
00:17:20.18 Tissues of the heart, for example, are also not turning over readily.
00:17:24.11 So, it takes years for them to turn over.
00:17:26.10 The liver, in 300-500 days, most of these cells have turned over.
00:17:31.25 So, there's a very, very quick drop in the carbon-14 that was found in these tissues.
00:17:36.13 Skeletal muscle, in months you're turning over these tissues
00:17:40.00 because you're using them all the time, obviously.
00:17:41.25 In blood, it's about 120 days for red bloods and 5 days for the gastrointestinal tract,
00:17:49.09 which is what I just mentioned to you earlier.
00:17:51.14 So, that essentially tells you one thing.
00:17:53.15 For example, I am 49 years old, but I know now that the average age of my cells
00:17:59.06 is anywhere between 7 to 10 years. So, even though I as an individual
00:18:03.10 am 49 years old, I have cells that were just born yesterday.
00:18:06.20 So, how old am I?
00:18:07.22 Alright, so these are things that we need to understand.
00:18:10.22 How do you integrate old with new, and how does the integration result in functional activities
00:18:16.22 that are normal and really don't know what these processes are
00:18:20.11 underpinning these events.
00:18:22.09 Alright, so, when Lewis Carroll wrote in Alice's Adventures in Wonderland
00:18:28.21 that "...at least I know who I was when I got up this morning,
00:18:31.16 but I think I must have changed several times since then."
00:18:34.03 Even though it was supposed to be non-sensical, it's actually true.
00:18:37.06 Oftentimes fiction is truer than we think.
00:18:40.08 And so we are really constantly changing on a daily basis
00:18:43.11 and it's important for us to think about this biology in these terms,
00:18:46.19 as a dynamic process.
00:18:48.22 Ok, so the second to last topic that I want to cover with you is regeneration.
00:18:53.24 Now, why do I want to make a distinction between tissue homeostasis and regeneration?
00:18:57.14 The distinction that I want to make is illustrated by this next slide.
00:19:00.24 It actually involves injury. Here is a situation where I'm using a razor blade
00:19:06.03 to amputate a planarian, which we're going to talk about in just a few minutes,
00:19:09.14 into three different fragments, ok.
00:19:11.10 So, when you actually are just undergoing normal, physiological wear and tear,
00:19:16.07 and those tissues are repaired by the endogenous stem cells,
00:19:18.08 you're not really introducing a physical injury that was introduced by a blunt force,
00:19:24.27 or something like that.
00:19:25.22 That usually happens in regeneration, and some organisms, as we'll discuss in a second,
00:19:30.11 are really good at repairing themselves after such types of injuries.
00:19:35.04 So, here's a planarian, you can see the head,
00:19:37.23 and so here, you can see the nice little eyes over there,
00:19:40.09 there's a trunk right here, with a pharynx in the middle,
00:19:43.05 and here's the tail down here.
00:19:44.20 And what we're going to do is that we're going to follow each of these fragments
00:19:46.18 through time.
00:19:47.24 So, here's the times, this is day 1,
00:19:50.08 day 3 and this is a marker that we use to measure cell proliferation,
00:19:54.10 and then day 7. So, if we look at the head,
00:19:56.10 this is what happens. You get an animal that heals its wounds,
00:19:59.15 by the third day, you see this little white tissue sitting here at the bottom,
00:20:03.03 that's referred to as a regeneration blastema,
00:20:05.17 if we look at that day, by mitotic activity, we can see a lot of cells dividing,
00:20:09.26 right near where this amputation plane was.
00:20:11.23 And by 7 days, the animal has essentially repaired or restored the tail.
00:20:16.06 That's fine for a tail.
00:20:17.04 What about the trunk? It has to regenerate both head and tails.
00:20:20.25 And so what it does is essentially the same thing.
00:20:23.25 It forms these healing at both ends, the blastemas at the head and the tail,
00:20:29.23 we now see proliferation at both ends of the animal,
00:20:32.20 and eventually, you get a head and a tail, essentially restoring the anatomy of the animal.
00:20:37.05 And the same thing is true for the tai.
00:20:39.12 The tail will actually going to form a new head by the same process.
00:20:44.04 So, regeneration activates this population of stem cells
00:20:47.03 to produce all of the different cell types that are required to restore or regenerate
00:20:52.07 all the missing body parts that were lost to amputation. Ok.
00:20:55.15 So, obviously, you and I can't do it.
00:20:58.17 I mean, not like a planarian could,
00:21:00.07 I think that the French already demonstrated with their French Revolution
00:21:03.04 that decapitation of human heads does not result in the growth of a new head.
00:21:06.25 Proved over and over. However, this does not mean that just because we don't do it
00:21:11.09 and only a few animals do it, it's just a rare event.
00:21:15.01 It turns out to be extremely, extremely broadly, but unevenly, distributed throughout nature.
00:21:20.00 You can go to simplest animals like anemones, for example,
00:21:21.26 you can cut them, they'll regenerate,
00:21:24.09 you can actually look at things that are a bit more complicated, like an octopus, for example,
00:21:28.19 those tentacles can be amputated, they'll actually grow back.
00:21:31.02 Snails, their heads, for many species, can be decapitated,
00:21:35.00 those heads will actually grow back as well.
00:21:37.08 And so these are animals that are fairly complex
00:21:39.05 and have essentially all of the tissue types that you and I have in our body.
00:21:42.16 You can go to animals that are closely related evolutionarily to us as vertebrates,
00:21:46.28 these are sea cucumbers, and they'll do something remarkable.
00:21:49.15 When they are attacked, what they do is that they literally
00:21:52.15 throw up their entire gastrointestinal tract such that the attacker can eat its guts.
00:21:58.05 And while the attacker is eating its guts, the sea cucumber just crawls away.
00:22:02.08 Then, after a few weeks later, it regenerates its entire gastric system.
00:22:05.24 So, this is an example of a patient in which regeneration plays a key role.
00:22:10.09 Then of course, there's the champion of regeneration which are these axolotls,
00:22:13.25 and salamanders. These are endemic to Mexico
00:22:16.08 and these animals have been amputated in a variety of ways,
00:22:18.24 the limbs will regenerate, the digits will regenerate, the jaw will regenerate,
00:22:22.18 these little gills right here will regenerate, the tail will regenerate,
00:22:27.10 and in many other species, people have tried to amputate parts of the heart,
00:22:30.13 which will grow back, kidneys, et cetera, et cetera.
00:22:32.29 So, their capacity for regeneration are truly, truly astonishing.
00:22:36.16 And this is a vertebrate. This is an animal that is similar to us
00:22:39.13 in the fact that we're both vertebrates, in that case.
00:22:42.13 Now, you could argue that the reason why this happens
00:22:44.20 is because all of these animals right here, you know, are small,
00:22:48.09 and they live in water, and maybe they're not terrestrial animals like you and I,
00:22:51.16 and they're not as big. But I think that the most remarkable example
00:22:54.23 of animal regeneration happens in a very close relative of ours,
00:22:58.10 which are the ungulates.
00:23:00.09 These are the deer.
00:23:01.18 So, any of you who live on the Western part of the United States
00:23:04.08 will have seen this. Every summer, or every spring,
00:23:07.25 these animals will actually shed their antlers.
00:23:10.18 And they'll grow them again.
00:23:11.28 And it's not like they're just growing a nail,
00:23:13.15 they're actually growing real tissue. So, these antlers fall off,
00:23:16.14 and that regeneration blastema, like the ones that I showed you in the planarians,
00:23:20.22 will form and these blastemas will be vascularized,
00:23:24.27 meaning that they will have blood, circulation going through it,
00:23:27.16 they will be enervated, means that there will be neurons in there,
00:23:30.01 and it will be ossified, and the bones will grow.
00:23:33.10 And so when this actually grows, and it grows incredibly fast,
00:23:35.25 then what happens is all of the soft tissues will undergo cell death,
00:23:38.29 they fall off, and now you have these beautiful antlers.
00:23:41.28 And they do this every year.
00:23:43.19 So, it's not like mammals cannot do this.
00:23:45.15 They can do it, but we just don't know why we can't do it.
00:23:48.01 So, we'd like to understand why that's so.
00:23:50.04 And so here's a tree of the metazoan tree of life,
00:23:53.07 the phylogeny showing you in green all of the phyla in which regeneration has been described,
00:23:58.25 and the ones in black it's not that they don't regenerate, we just don't know
00:24:02.02 whether or not they regenerate or not.
00:24:04.18 So, with all of this remarkable biology, how can we get to mechanisms?
00:24:09.02 How can we study stem cell functions?
00:24:11.00 So, I'm just going to go through a few slides now to give you an example
00:24:13.27 of how we actually try to tackle this problem using planarians.
00:24:17.17 The first thing that you need to understand is that whether you look at a planarian,
00:24:20.18 or whether you look at a budding yeast like this,
00:24:23.02 the amount of genetic information that's shared among all individuals on this planet,
00:24:27.15 all living forms on this planet, is extraordinary.
00:24:29.25 For example, there are mutations that you can introduce into this yeast
00:24:33.17 and they will actually cause malfunctions in the fungus, in the yeast,
00:24:37.16 and it'll just not do well, it'll die.
00:24:39.16 However, you can take DNA from humans, put it back into this yeast,
00:24:44.10 the same genes that you and I have, put it back into this yeast,
00:24:47.00 and rescue that mutation and rescue the viability and the life of this yeast.
00:24:50.28 How is it possible? Well, it turns out that there's about a hundred human disease genes
00:24:55.14 that are found in our genome that can actually rescue the corresponding yeast gene mutation.
00:25:02.00 If you think about this, the evolutionary distance between humans and yeast is not a couple of days,
00:25:07.12 it's about a billion years. So, how can these functions be so incredibly conserved,
00:25:12.09 so deeply conserved between such disparate individuals,
00:25:15.28 and that's because these principles of biological development
00:25:18.28 are actually shared by most organisms.
00:25:21.14 So, what we can do then is take advantage of the stem cells that are found in humans,
00:25:25.12 take advantage of stem cells that are found in other organisms like planarians,
00:25:28.18 compare the genes that regulate both of these processes,
00:25:31.12 by looking at their DNA, and try to understand how the cells do what they do,
00:25:36.04 and then try to learn about this biology, more about ourselves.
00:25:40.07 So, I'll give an example.
00:25:41.12 Here's a situation where we can actually change the fate,
00:25:43.29 I mean, what the cells are going to make after amputation.
00:25:47.01 So, what we do is that we take advantage of what's known as a signaling pathway,
00:25:50.25 in this case the Wnt/beta-catenin signaling pathway,
00:25:53.02 you can look this up in your textbooks.
00:25:55.28 So, what you see essentially is that I'm going to talk about two things:
00:25:58.04 the activator, right here, and the inhibitor of this pathway.
00:26:02.01 So, this one is just going to affect the functions.
00:26:04.11 If we get rid of the activator by a process known as RNA mediated genetic interference,
00:26:09.15 or RNAi, what we see is quite remarkable.
00:26:13.01 So, here's the normal situation.
00:26:14.04 The control experiment. You amputate the animal
00:26:15.26 and then what you see is what I've shown you before, each of these individual animals
00:26:19.17 will actually go on to make the missing body parts, ok.
00:26:23.07 So, that's the first thing. If we now get rid of this activator, the beta-catenin molecule,
00:26:28.02 now crossed out by red, what you see if that we amputate the animal,
00:26:32.08 and now instead of getting animals that regenerate a head and a tail at both ends,
00:26:36.04 they regenerate heads at both ends.
00:26:38.10 We essentially just changed the fate of what these cells can make
00:26:41.19 by simply eliminating this particular molecule, this beta-catenin.
00:26:44.29 Now, this is a very old signaling pathway,
00:26:47.05 we find it all the way down from jellyfishes,
00:26:49.07 all the way to humans and its conservation is absolutely astonishing.
00:26:52.28 Now, we can also do the following, which is, what if we allow the activator to accumulate,
00:26:58.03 by eliminating the inhibitor.
00:27:00.08 So, we do that experiment and essentially what we do is that we get rid of the inhibitor,
00:27:04.14 allowing the activator to accumulate,
00:27:06.18 and when that happens, then after amputation, this is what we see.
00:27:11.01 We essentially see that the animals, instead of now regenerating heads,
00:27:14.26 they regenerate tails at both ends.
00:27:17.19 You can see that right there.
00:27:19.12 So, that suggests to us then that these particular pathways
00:27:21.29 absolutely are required for the maintenance of the head and toe,
00:27:26.12 so to speak, head, anterior-posterior axis, of these organisms.
00:27:30.28 Now, amputation is not what activated this particular pathway,
00:27:34.15 you can actually do this without cutting the animals.
00:27:36.22 So, we can now get rid of the activator again,
00:27:38.17 not cut the animals, and now you get animals that essentially grow heads
00:27:41.29 almost everywhere where there is a dorsal-ventral confrontation,
00:27:45.13 at the edges of the animal, right here.
00:27:47.23 Ok. So, I want to conclude by essentially driving home the following points.
00:27:52.10 The first is that understanding of stem cells in vivo is really limited.
00:27:57.22 We really don't know what these stem cells are doing throughout the process of embryogenesis,
00:28:02.09 throughout the process of fetal development,
00:28:04.18 during post-birth, growth and old age,
00:28:07.17 these cells are playing roles in all of these stages, but we don't know with precision
00:28:11.11 how they do what they do.
00:28:12.29 Secondly, we need model systems to overcome these limitations of knowledge; clearly,
00:28:17.09 we should not and will experiment with humans,
00:28:19.28 but since this biology is so deeply conserved between us and every other living organism out there,
00:28:25.17 we should be able to learn lessons from these organisms
00:28:29.02 on how they do what they do.
00:28:30.16 Next, I think that many organisms, including planarians,
00:28:34.10 share this high degree of genetic homology with humans,
00:28:37.03 that it's going to allow us to understand our own biology
00:28:40.04 by just simply studying these particular processes.
00:28:43.09 Then, it's also possible, as I showed you, to manipulate the in vivo function
00:28:48.23 of these stem cells and their environment in organisms like planarians,
00:28:52.09 particularly, other model systems that can regenerate new stem cells to do this.
00:28:57.05 So, there's an enormous breadth of biological activities
00:29:00.18 that can be uncovered in these model systems
00:29:02.28 and extend, again, to our understanding of our own biology.
00:29:05.19 And finally, I think that model systems like planarians really provide unique
00:29:09.22 and unexplored opportunities to understand stem cell biology
00:29:13.16 and the roles in tissue homeostasis and regeneration.
00:29:16.17 So, with that, I'll leave you with this talk
00:29:18.28 that there is much to be learned out there,
00:29:21.12 there are many things that we don't know anything about
00:29:23.25 and that much work needs to be done
00:29:25.13 in order for us to begin to understand not just our own biology,
00:29:27.28 but our relationship with other organisms and biology at large.
00:29:31.11 Thanks very much.

This Talk

Speaker: Alejandro Sánchez Alvarado

Audience:

General Public
Educators of H. School / Intro Undergrad
Student
Educators of Adv. Undergrad / Grad
Researcher
Educators

Recorded: July 2013

Talk Overview

In one year, each of us will lose and replace a mass of cells equal to our own body weight. It is only because these processes are closely regulated that we can recognize ourselves as the “same” person after that year. Sánchez Alvarado explains that tissue homeostasis and regeneration are regulated in part by stem cells and he argues that studying model systems such as planaria will allow us to understand the role of stem cells in human health and well being.

Speaker Bio

Alejandro Sánchez Alvarado

Dr. Alejandro Sánchez Alvarado is an Investigator at the Stowers Institute for Medical Research in Kansas City, MO and the Howard Hughes Medical Institute. He is also co-director of the summer course on embryology at the Marine Biological Laboratory in Woods Hole, MA. Sánchez Alvarado moved from Venezuela and received his Bachelor’s degree in Molecular… Continue Reading