Episode Notes for
Monsters from the Lab
Blake Smith: There’s a movie called Splice coming out soon which deals with a new form being created by splicing human and animal DNA. The film Species dealt with a similar idea only it was alien DNA being spliced with human DNA. And the 1970’s film Prophecy dealt with pollution causing birth defects creating a monstrous bear. It’s not new ground in that, in the movies, as in real life, genetic modifications often have monstrous results. But what is a monster? And what if your job is to make them – not in a fictional sense, but in real life? What are the ethical boundaries of science and what constitutes a monster on this episode of MonsterTalk.
Blake: I’m Blake Smith and this is MonsterTalk sponsored by Skeptic magazine. Today, my co-hosts Ben Radford, managing editor of Skeptical Inquirer and Dr. Karen Stollznow, blogger and host of Point of Inquiry, interview Dr. Marcus Davis, a biologist at Kennesaw State University. Dr. Davis participated in the famous Neil Shubin Tiktaalik dig and he performs genetic and embryological research in his work on comparative anatomy. As he puts it, making monsters is part of his job. His interview is chock full of good information so we’re just going to hop right in.
Blake: You are an evolutionary biologist and you teach at Kennesaw State University.
Marcus Davis: That is correct. When people ask, I tell them I’m an evolutionary biologist first, and then after that I say that what I’m really interested in is the evolution of development and how the developmental program for building organisms has itself evolved over time.
Blake: So the development of development? That’s very meta.
Marcus: That’s too meta. The evolution of development. I could also say the evolution of evolution in a way, too. That’s even more meta.
Marcus: In a way the development of development over time – how that program has changed or, in some cases, not changed because sometimes it’s very conservative. I’ve focused on the vertebrate skeleton; so most of my research has been on the vertebrate skeleton: what patterns do we see, what patterns do we not see, what genes are involved and then I use what’s called the comparative method, which is I look at not just one organism like say a mouse or a zebra fish, but I look at as many organisms as I can get my hands on and I compare them and say what’s different and what’s the same.
Blake: How much of your job is done through say skeletal examination versus genetic examination?
Marcus: Well, those are hand-in-hand in many ways because genetic and skeletal are two sides of the same coin. Behind what we call the phenotype, which is the binal product, the morphology of an organism and its function, something like the skeleton is a genotype, which is the sets of genes that code for that phenotype. You’re really doing an analysis on both. When you are looking at a gene and asking well, what gene in involved, when is it turning on, to what degree, how is it being modulated during the development of an organism, one of those questions you’re asking is what structures is it making? So really I’m doing both; I’m analyzing skeletons and asking what genes are behind those skeletons. It’s hard for me to parse those out because they both go into any analysis I do.
Blake: Well, the reason we have you on tonight is because I heard you at the lecture that was put on over at the university by the Student Coalition for Inquiry. Part of your talk we were discussing…well, you were discussing, I was listening…kind of a one way…
Marcus: …one-way discussion…
Blake: Right…you were discussing the development of creatures and part of that conversation got me thinking about the work of Jack Horner and his new book about the idea of recreating dinosaurs from modern day birds using different techniques.
Marcus: How to Build a Dinosaur.
Blake: How to Build a Dinosaur. You seem to have a lot of opinions about that you didn’t actually go into during your talk and I thought maybe we could discuss that and monsters because that’s what the show is about.
Marcus: And I make monsters and I’m interested in them so that sounds fine to me.
Blake: Cool. So making monsters. Specifically, as we were leaving the talk, you gave a brief history about the word monster and how it pertains to science.
Marcus: Right. Well, first off, if you actually look at the Latin root of the word monster, there’s a Latin verb “monstrare” which actually means to show or to point out or to reveal, something along those lines. It’s actually the root for the word “demonstrate”, which has monster embedded in it. And in fact, you can’t spell “demonstrate” without “demon” attached to the beginning of the word and a demon is a type of monster, is it not? And so really what monsters are and the first usage of the word was in medicine and pathology as a term for an organism that was born in an unexpected way. It was in someway abnormal, grotesque or born differently. We think about monsters as being, you know, you think of Frankenstein’s monster, something hideous or abnormal that’s not going to fit in, but you can think about what you learn from it, the “demonstrating” part, which is what you can gain as far as knowledge about how development works. We learn in science often by seeing how things go wrong. We don’t build atom builders, we build atom smashers; we slam stuff together and look through the pieces. That’s much of what we do in development is we look at what happens when development goes wrong and ask, well, what went wrong and why. And so a monster, the classic use of it in pathology, was an organism that in some way demonstrated something about how development or embryology proceeds by showing you how it can go wrong.
Karen Stollznow: I’m a linguist. I had no idea about the etymology of the word monster. That’s really fascinating.
Marcus: Yeah, it’s kind of a cool thing. I actually learned that from Scott Gilbert; he’s sort of the poet laureate of developmental biology. He wrote the classic textbook that’s used in undergrad classes around the country. He’s a bit of a historian of the field beyond just being a great biologist. I always thought that was cool.
Ben Radford: You were talking about how what differentiates a monster from a supposed normal phenotype, but, of course, you have normal variation, so you’ve got a wide variety of variation within in a standard type. Where does one draw the line between a monstrously large person and a tall person or a dwarf or something else? Where would you draw that distinction?
Marcus: You know, one man’s monster is one environment’s innovative phenotype in that there’s this concept of a “hopeful monster”, if you will, that was coined by an embryologist, Richard Goldschmidt, many years ago, in the last century, that that’s what variations in phenotype are. When mutants or variants appear in a population, they may be “hopeful monsters” in the sense that the variants in their phenotype; their function, their behavior and whatnot, may actually in some way make them well suited to a changing environment. So really when we are looking at monsters in a lab environment, we may be looking at the extremes of natural variation, but we may also be looking at things that go beyond those extremes that actually become what we call deleterious; they go beyond being potential fitness advantages, in some other environment, to being actually clearly harmful. Obviously, if an organ, or part, is completely missing in an organism, that could be very detrimental to its well being, if it’s not developing normally, then those sorts of monsters are in the extreme and they’re the type you would think of being not viable.
Ben: That would be different in kind than a monster simply being an organism that hasn’t adapted to its environment.
Marcus: Right. It’s in degree; are we talking a one percent monster or are we talking a fifty percent, I suppose. A monster may simply be a bit of a suborder variant, a larger size, a slightly different color pattern, a novel behavior that appears. If you want to interpret that way, a new behavior appears in a population, you could talk about that in terms of being a monster variant; it is abnormal compared to what you would call the standard population mean behavior before. It is something of a value judgment we throw on the word as humans of looking at it in terms of it being grotesque or not viable, but I like to think the word monster also from the positive, the “hopeful monster” side, that those are the natural variants in nature. You have to remember that it’s in the context of the environment; organisms are simply adapted to the environment they are currently in. The environment changes, what was a great phenotype in one environment could suddenly be a poor phenotype and suddenly the abnormal variants are now better suited; the ostracized, if you will, the monsters could suddenly be the new, successful phenotype.
Karen: What about in popular culture, how do you think that’s different to the way that the public views the idea of a monster?
Marcus: Ah, well, we could probably have an entire series of discussions on how fringes of groups are ostracized simply for being different and how, by the very definition, the core of a population follows a set of core behaviors. And so I think monsters are often viewed as simply being the radical fringe in appearance or behavior or in thought that can make freethinkers and other people with big ideas monsters of ideas as well. In that regard, monsters can be anything that makes you uncomfortable, anything that upsets the applecart or changes paradigms potentially. But I like that idea of a monster then. But that’s just me.
Blake: You mentioned that you create monsters. How do you do that?
Marcus: My biggest set of questions is, how does a vertebrate build its skeleton? Vertebrates, of course, are the back-boned animals; this includes all the fishes and then all of us animals that have come up on the land, which are basically fishes as well; we’re just very modified terrestrial fishes with all of our special adaptations for being on land. When I look at the developmental program for all of these animals, I see an awful lot of conservatism. Most of the same genes that are involved in making the skeleton of a fish, even a primitive fish; a living primitive fish like a shark, for example, uses pretty much the same sets of genes and those genes are in the same place and turn on in very similar ways and at similar times to the genes that turn on to make my own skeleton as a human. We actually don’t do research on humans, though we use mice as our proxy, as our approximate human being a mammal, and I see this remarkable conservatism in this skeletal pattern between these organisms. Because there’s this commonality of plan, one way I have to understand how that structure is built, is to try to perturb it, to push it off of its normal program, if you will. To do that, we have to block the function of a gene. We have turn it off, we have to gum it up, we have to use a chemical perhaps that blocks its signal and see what it actually it does to the phenotype of the organism and from that we can backtrack and infer something about the function of the gene. Now ideally, we have a set of checks and balances; we use more than one technique and hopefully be getting some results that match up to allow us to infer something about gene function. In my own work, we use different techniques that will inhibit or block the function of a gene or we may go the other route. We may actually turn up the volume on a gene and actually over-amplify a gene; make a gene come on earlier than it normally would in development or stay on later or, as I’m fond of saying, turn the volume up to eleven instead of where it should be and see what those results are as well. The results are sometimes the production a novel phenotype or a monster; you get a shark or a fish that has structures that are bigger than they should be or they’re in slightly the wrong places or sometimes radically wrong places and you get some rather monstrous looking phenotypes.
Ben: When you do that is there an ethical issue involved in intentionally creating monsters? If one of the products of what you’re doing is having a living, sentient being that is in some ways intentionally deformed, certainly for its environment, is there an ethical issue with that? How do you address that?
Marcus: There is definitely an ethical issue. I think the first thing that you will find is that no one can take this type of research with more of a solemn and serious attitude than the researchers that are involved themselves. I’ll speak for myself, but I know from many of my other close colleagues, we’re some of the biggest fans of the organisms we work on; we are very close to these organisms. In many ways, we recognize that these organisms are paying an ultimate price to provide us with knowledge. I’m always reminding myself and my students these organisms are giving up their existence so that we can learn something; don’t be wasteful of that opportunity. We also need to do whatever we can – we can talk about some of the infrastructure that’s put in place to insure that things are done ethically and humanely – we’re always looking for ways to minimize anything we might consider to be suffering in organisms. And then something else the general public may not be aware of, we’re not taking organisms to full term. For example, the fish that I work on, the formation of their little skeletons, I’m not raising these fish with extra structures or head parts that are missing or such, up to adult fish that are swimming around savvy in a tank like something out of Alien Resurrection or something. They are, as larva or embryos, as soon as they provide a phenotype to register what the function of the gene is; they’re being put down humanely – sampled as we call it – because the idea for me, frankly, of having an organism sitting around suffering unduly, once the data is available, is simply unacceptable. It is unethical. That is generally the view you will find among researchers in the field that are working intimately with these animals.
Blake: Are there governing bodies that guide that?
Marcus: There are various governing bodies at different levels, and frankly, there has to be some better unification at an international level to try to unite these threads of governing bodies. There are two different paths of ethical concerns that pushing forward what’s allowable in path breaking biological work in cells and development and such. One is, and this is what’s pushing forward ethical questions, stem cell research and especially the use of human stem cell research. At an international level you have things like the United Nations, the World Health Organization. There’s a council in Europe, it’s a convention on human rights and biomedicine, and they’ve at least made statements about would should be limitations on human stem cell research; they don’t necessarily agree with each other in having a plan as to how to enact those. At a hands-on level though, particularly in this country -- there are different rules in different countries, some are not are well policed as others -- but in this country, there are actual sets of regulations and government governing bodies to insure that animal welfare and research is being considered. The main one is the National Institutes of Health, which is a government agency, has an Office of Animal Laboratory Welfare called OLAW. OLAW oversees something called IACUC, the Institutional Animal Care and Use Committee. If you are at an institute that is doing research on organisms, you have to have an IACUC organization protocol, and this is going to involve a committee; there’s going to be external oversight for this committee; there’s going to have to be written protocols for how you are going to use your animals and people are going to come in and make sure you are using them properly. Part of the safety check also is that to do research on animals you’ve got to have money and money comes from grants and to get a grant you’ve got to have IACUC numbers, basically you have to have approval. You’ve got to demonstrate that you’re going to use the animals humanely before anyone will give you research to even use the animals. That tends to be the primary mechanism for making sure that someone’s not out there doing the sort of South Park making five hind-ended monkeys.
Karen: In which countries would the regulations be a bit more lenient and have there been any problems that have ensued?
Marcus: It seems like in emerging industrialized countries; I think the area that is a bit of a question mark is going to particularly be in places such as China and some of the other surrounding Asian countries that are just bringing up path breaking research. Japan has been on-board for longer and you can treat them in the same vein of having an organized system like Europe and North America has. There are some question marks about exactly what are the ethical standards for animal research and actually what may be going on; I’m not proposing any conspiracies about them building Godzillas or anything over there, but I don’t know what kind of infrastructure they have for animal welfare in some of these countries or if they do yet and that’s a big question that needs to be addressed. Of course, there have been some high profile issues coming out of some of those countries; the ones you hear about most again come back to things like stem cell research. One of the big ones, and, of course, this was really not about an ethical issue regarding the actual use biological material, but there was a researcher, Hwang Woo-suk, who back about five years ago now, claimed to have actually created human embryonic stem cells using therapeutic stem cell technology and got a bunch of this stuff published. And then it turned out a bunch of his research was fabricated and he ended up admitting to the fraud and being expelled from his university, although apparently he was rehired elsewhere right after that suggesting that there may not be some of the safety checks in some of these other countries. It’s kind of hard to pull one over on the research community and the organizations for funding and for supporting animal welfare, at least speaking for what goes on here in the U.S. I can speak for myself; I’m at a university that’s just now starting to emerge with a serious research program. We can’t write big grants to do animal research unless we have all of our ducks in a row as far as all of these animal care regulations; we have to have all those numbers, all those people on-board before anyone is going to give us money to do the real research.
Blake: That raises an interesting question; does that mean anybody who wants to do replication of these experiments have to go through the same regulatory bodies?
Marcus: Yup. That’s really the case.
Marcus: Now if you have Bill Gates to do something underground – if Bill Gates is listening, no offense – to do the Jurassic Park-way with some crazy rich guy to bankroll everything and you want to do it off the grid, I suppose there’s nothing to prevent something like that from happening. Although, if you’re going to do research off the grid, you’ve unplugged yourself from the power of doing science, which is the fact science moves forward because we have the power of numbers; we interact as a community and that’s what moves us forward, which I’ve always said is the biggest argument against there being secret science being done because when you unplug from the community, it’s hard to move forward in isolation. I imagine you could do some secret work hidden down deep in a mountain somewhere if you really wanted to clone monkeys.
Ben: That reminds me of the whole cloning thing with the Raëlians. It’s exactly the sort of the same thing where Claude Vorilhan, the head of Raëlians…oh, yeah, we clone people. It was sort a self-contained sort of James Bond villain type of scenario.
Marcus: It’s funny you should mention Raël because I knew of that guy when I was a kid. I’m actually a motor sports fan that who used to race sports cars, so I knew this crazy guy who had some cult as this guy who used to drive a Lotus back in the 80s and it’s funny, I still talk about him in this totally other context in my life now. It’s like I tell my students, too, I use the sports analogy; in sports, it’s really not smack talk if you can back it up on the court. In science, the comparable thing is data; if you’re going to make an assertion, you better bring the data. It’s not smack talk, if you can back it up with data. They’re just talking smack. You want to make an assertion, you’re over there cloning human aliens, fine, just bring me the data, I’ll look at it.
Ben: The thing that surprises me is just how long it goes without people bringing forth the data. You talked about Woo-suk or, for example, you look at Pons and Fleischman with the cold fusion stuff; they kept that up for years, as I recall, and finally it all imploded. It’s remarkable how long some of these things take to finally be exposed.
Marcus: You also get the component of other people trying to replicate results and getting negative results and being a little fearful of jumping right in there and saying, well, I didn’t get their results, so they must be wrong. If you’re going to go take them to task, like the cold fusion guys, and say, you guys made this up, that’s an extraordinary claim, so you better be pretty confident in your extraordinary evidence, which, frankly, is negative evidence; we could never get it to work. So there can be the slow going of, well, we’re going to have to kind of sit here and wait until a whole bunch of labs also continue to get nothing before we actually call them on this.
Ben: It reminds of Andrew Wakefield, the anti-vaccine doctor; he was finally kicked out of medical practice, another example.
Marcus: It can be slow going. It can be slow going to refute a big claim, even when it’s kind of clear that the data is not really there. It takes the community action and because we’re skeptics and we’re cautious; we don’t like to jump the gun. It’s funny, but it always does take some time.
Karen: And then the damage has already been done.
Marcus: Yeah, the damage is done, especially because the general public remembers the hot button issue and they don’t hear about it when it gets refuted later. I’ll use an example from something I lecture on quite a bit because it’s close to my own research – the origin of birds. Birds are dinosaurs; you don’t turn a bird into a dinosaur, a bird is a dinosaur, in the same sense that you and I are mammals. We evolved out of mammals; once you’re in the club you’re not allowed out. Birds evolved from dinosaurs and that makes them dinosaurs. Our fossil evidence for this is gorgeous and wonderful. I wish Darwin was around to show it to him, he’d love it. But I’m struck by how people come up to me and say, well, I thought that was all refuted because they found that forgery. And the fact is, among the hundreds of different specimens of feathered dinosaurs among dozens and dozens of different species now found over the last fifteen years, there was a single incident of a specimen that had been glued together from two separate specimens by a farmer and sold to some not very well experienced scientists that misinterpreted it; they kind of got duped by a farmer that made a really nice specimen out of some junk. I’m struck by how many people just took that one incident; they heard this was all a forgery in the same sense that hear people talk about Piltdown Man still and say, well, I thought evolution was invalidated because there was that Piltdown Man thing. I’m like, really, that’s so 1890 of you. But those things really stick in people’s minds; a single incident of something, like a stem cell researcher being fraudulent, is enough for people to cast doubt on the majority of a community at times. It’s something in human nature.
Blake: Well, they’ve certainly done a number on the human cloning. It seems like all of the examples we have so far that have been in the media have been fake, right?
Marcus: Yeah, what a person not in science hears is the stuff that comes through the media and the media, of course, is focused on the sensational stories and sensational stories are often stories of tragedy, intrigue, or accident. And so there’s going to be preferential treatment towards things that are sensational, especially something that is fraudulent in the same vein that people are afraid to fly because they say it’s dangerous to fly because planes are always crashing, but that’s because planes actually rarely crash. So when they crash, it’s big news. But cars crash all the time in every city, every day and you never hear about it because it’s such a common story no one reports it and so people forget it’s more dangerous to drive to the supermarket than it is to fly somewhere. In the same sense, if you are not hearing all the stories about work being done in an area such as stem cell research because most of it is kind of boring and just detail oriented progress being made and occasionally you hear some sensational story, you maybe take that as representative of what’s actually happening instead of being the outlier, which is what it really is.
Blake: With the ethical limits and the governance limits, what do you think are the literal limits of what we are going to be able to do with embryological and genetic manipulation?
Marcus: Well, I’m going to avoid that question in a sense because I was at one point a physics major as an undergrad and there’s a long history in physics of famous physicists – I’m not claiming to be famous here – but a famous physicist getting up at conferences and saying, in ten years we will have described and discovered everything there is to discover in physics, and those people always being completely and totally wrong. I’m not even going to hazard a guess as to where the limits in our ability to understand organisms and to design, to manipulate, I don’t know if I want to use the word control, but to modify development, to understand it, lie. I don’t know where those limits lie. I will say that I believe we’ve only begun to scratch the surface in understanding how genes actually interact with each other; it’s still very early days. This is one of the issues I do have with some of the stuff that you hear out there, such as Jack Horner’s book How to Build a Dinosaur. We don’t understand much of the subtlety about how genes interact, in time and space and concentration, to actually build an organism. We do understand at a very rough, approximate level. We have this sort of basic tune in our head, if you will, but we are not ready to manifest it into concertos at any level yet. Nor do we have the tools for putting all those genes together and getting them to interact the way we would like to. We can play with a few genes at a time, but building whole chromosomes, stacking chromosomes together, sticking large numbers of genes from one organism into another and getting a functional organism, are things that are way down the road. A lot of our paradigms are turning over very quickly right now. You’ve heard about junk DNA, right? The textbooks still are full of talking about, well, there’s a lot of DNA that’s junk and isn’t being used; that’s radically, very quickly being erased. We’re finding that, yes, there’s some debris and junk in our genomes; there’s some stuff in there that is artifacts, sunken ships of genomes past, if you will. But much of that architecture, things that do not code for proteins, in other words, they’re not genes themselves, are still absolutely crucial for genes turning on at the right time, at the right concentration, for being modulated properly; a lot of that stuff that you might think of as junk DNA is actually spacer DNA and organizer DNA and plays some sort of blue collar roles, if you will, ensuring that all of those genes get expressed properly. We’re just really starting to get a sense of how elegant and complicated that system is. It’s going to be exciting times; there’s much more for us to explore, but I wouldn’t say we’re anywhere close to saying what we’ll be able to do. Maybe build and organism from scratch at some point; maybe build a dinosaur from scratch, in silicon, on a computer, and ultimately have an organism that’s live like another? Why not? That’s down the road somewhere, but are we anywhere close to that? No, not in the slightest.
Ben: I think one the things that happens is that the general public gets very impatient because they hear all these stories in the news that are new things and embryonic stem cell research and these sorts of things. And what people sometimes forget is that this is a very new science; this is not something people have had two hundred years to work out. You guys are working on things in the field that have only been around for a few years. It’s remarkable to me that people have such a small focus on what you guys are doing.
Marcus: That’s true. In fact, in some ways, all science is new science. Once it becomes old, it becomes part of commonplace technology; we integrate into the rest of civilization; it’s no longer sort of the leading edge, breaking path. The stuff you hear about is always work in progress and is brand new stuff. As answers start to emerge, we publish so that everyone can start discourse on this and that sometimes gets into the mainstream media when it’s interesting or sexy enough, but that doesn’t mean that we have it all worked out. We have a new piece worked out that may be sometimes allows us to answer a question; sometimes all it does is generate ten new questions or make us realize that we didn’t know that little bit, but now we know a little more about what kind of questions we should ask. I agree, it can make people impatient. You hear a lot of people say, what are you scientists doing? You guys are getting money, why aren’t you solving all the problems? We’re trying. It’s about the best we can do; it’s about the best science has always done. There are too many questions out there to solve them all overnight. We make progress at the rate we can make progress.
Blake: The work you do with embryos…how do you do a knock out gene, for example. How does that actually happen? What do you actually have to do? Is it hard?
Marcus: Yes, it can be, but there are various ways that you can actually go about…you mentioned a knock out gene…let me backtrack from that just a little bit. The goal here is to some way affect normal development and see what happens, in other words, in the spirit of the word as I defined it earlier, to “demonstrate”; to build a little bit of a monster here by seeing what happens when you tweak a gene one way or the other. You can do that in different ways. You could actually remove a gene from the genome; try to just knock it out, get it out of there, so it can’t actually turn on at all. You could instead find some way to molecularly gum up the works so the gene is actually in there, but can’t be expressed. And sometimes there are very simple ways to do that. There may be actual chemicals that you can expose the cells of the embryo to that will actually inhibit that gene and prevent it from forming. Or you may not even have to inhibit the gene; you may actually just inhibit the protein. Every gene makes a protein; that’s what a gene does and that protein builds something or does something in the organism. So if you have a chemical that, in some way, breaks down or stops or binds up the protein, you get the same result as if the gene had never been turned on before. So sometimes you can go about it in simples ways. If you do happen to have a compound, it can be something as simple as a plant toxin. We know that there are chemicals such as alcohol that can affect development. You hear about fetal alcohol syndrome, for example, has affect on the phenotype of babies that are born; it affects the development because that alcohol might have been in the mother’s bloodstream and ended up in the child’s bloodstream and ended up affecting gene expression. And so we know that some chemicals, a thing like plant toxins, caffeine is a plant toxin, for example, can affect development. So sometimes you can simply knock out the effect of a gene by literally soaking an embryo in a particular compound. That’s one of the easy ways to do it. If that’s not going to work for you, or you need something more precise, or you don’t have a compound that’s known to affect the gene you’re after, then you may have to actually go in and precisely excise, with a molecular scalpel, if you will, cut that gene out of the organism and that can get pretty tough to do. In fact, it’s so tough that we only have a couple of organisms that we use in research that we’ve developed enough as a research tool that we can actually go in and cut genes out. That’s what the actual knock out technology is about is to build what is called a transgenic organism where we have, in some way, added/removed a gene. To do that you have to use a little bit of genetic trickery; you may get some bacteria involved to help make copies of the gene. Usually it involves ultimately getting some modified copy of a gene into a stem cell from that organism; let’s say a mouse, because mice are used very commonly as knock out organisms. And then that stem cell will be inserted into a developing mouse embryo; basically we’re using cloning technology where we’re adding a few cells to this embryo that had had this extra gene, or a cut out gene, or knocked out gene in it. What will happen then is this embryo that has a few cells that have had the genes knocked out, if you do that with enough embryos, some of those embryos with the gene-lacking stem cells, those stem cells will end up in the germ line. In other words, they will end up making the sperm or the egg of that little developing mouse embryo, so that when it grows up, it will have either sperm or egg that actually lack that gene. In the next generation, if you breed some of those with each other, you can end up forming a generation of mice that completely lack that gene altogether. At that point, you have a knock out mouse. So, it is a bit of a pain in the butt. You’ve got to do some genetic manipulation, some stem cell technology, and then you’ve got to become a mouse breeder for a few generations until you end up with a mouse line that breeds true for this gene that is lacking. And then you can start doing the study of what’s the phenotype of this mouse.
Blake: Speaking of mice, we’re hearing something in the background. Do you have mice or typing or something in the background?
Marcus: Yeah, it’s gerbils running around. I just turned them off.
Ben: You turned off your gerbils? What are you doing with gerbils?
Marcus: They’ve been removed. There’s always monsters running around somewhere.
Ben: Let me pick up on that. At one point, I saw a photograph of a mouse with a human ear on it. It looked real, but, on the other hand, it looked Photoshopped.
Marcus: No it’s not. It’s not Photoshopped. Nor is it a mouse that has a genome for a human ear; it’s not developed that way. What you saw on that…and I know that’s something that has stuck in people’s mind and they think that you can get a mouse grown from an embryo with a human ear growing out of its back and that’s not the case at all. That was a mouse that was acting as a surrogate, or a template, for growing a big piece of cartilage for a prosthetic ear. The cartilage for that ear was actually grown on a template, basically a mold that was shaped like a human ear, that either was embedded in the mouse originally or the cartilage was grown on that and then embedded in the mouse and the mouse’s skin on its back was simply incubating it. So the mouse was acting as a host for basically a parasitic, prosthetic cartilage fake ear, if you will. While, yes, very interesting in its own right, there was nothing in the mouse’s genome that was driving the development of a human ear; we’re nowhere near that. If you ask me, so what are the genes that make the human ear, I might come up with a list of some genes involved, but I wouldn’t be able to give you the list and say these are the exclusive list of genes and, if you turn these on in a group of cells, you’ll make an ear. We’re nowhere near that level of sophistication yet in saying that these are ear genes to the exclusion of everything else.
Ben: If I wanted to have my own mouse with an ear on it, where would I get one?
Marcus: Um, check Walmart first. That’s usually the best bet…Super Walmart.
Karen: What else is that same process used for?
Marcus: The mouse ear thing?
Marcus: This idea of using a template or framework to entice cells to grow into particular structures is being explored with the idea of perhaps being able to actually grow organs in vitro. I know there’s some progress in trying to sort of build prototypes of some simple types of tissues, such as bladders, for example, which has been picked because it’s a rather tubby simple organ in some ways; it’s kind of just a sack to hold urine. In some ways it’s a little bit of a copout. What we’ve got to learn how to do is figure out how to send cells the molecular signals to actually form up into a shape like that instead of providing them a piece of plastic to grow on, but it’s a first step. A lot of this is about exploring what kind of signals are required to get cells to grow into particular shapes. In fact, if we learn what kind of signals it requires; does gravity in any way affect a cell, does contact with another cell affect it, does the amount of liquid around it, or electricity, or anything else affect the cell, might help us track down what genes are actually involved ultimately in telling a set of cells, hey, you guys that are there in a sheet, you need to fold up and form a kidney, or a bladder, or an ear, or any other structure.
Blake: We had Steve Jones on a while back and he was talking about how in the 80s it seemed like we were on the verge of really breaking in and learning a bunch of stuff. Instead, we basically learned we were very ignorant when it comes to genetics. I feel like a lot of the dreams that were really popular in 1970’s science fiction were things like using retroviruses to genetically alter living people. And now it seems like maybe that is not very bloody likely.
Marcus: Isn’t that the case with all of science? I haven’t seen the flying cars that were promised yet either, although considering people’s inability to drive in two dimensions, I’m not sure about adding a third to that being a good idea anyway.
Blake: But we finally got jetpacks! I’m really excited about that.
Marcus: You personally do?
Blake: Well, I don’t have the money right now, but I guess some guys in New Zealand have got one; I think they said it was $75,000 and you have to take a training course.
Marcus: If you can get me a jetpack, I’ll get you a mouse with an ear.
Blake: Hey, now we’re talking!
Ben: That’s a fair swap.
Marcus: I think that’s always the case in science. We have a view of where we are and we extrapolate with a dashed line to where we think we will be. That’s why I was so unwilling to answer your question of exactly where we’re going to end up with all this genetic manipulation. So we say, well, we’ll be able to do this and then we probe a little further with our technology and understanding, and we realize, well, there’s another tier to interaction here. I think we keep underestimating the levels of subtlety of interaction of components in this universe, in a sense. We’ve done this in physics, as well. We keep thinking we’ve reached the end of atomic and sub-atomic particles and how they interact with each other. Now we’re on this quest for dark matter and dark energy and for structures that may not even register the way we’ve been recording it up to this point. In some ways that’s happening as we probe into the genome further. We’re realizing that are these secondary and tertiary levels of interaction that we hadn’t even imagined to be there. We have to say, hold on a second, we didn’t even think about this. I’ll give you an example of that. One thing we started to realize, as we started to actually do these genome projects and count up how many genes are in organisms, is there’s not enough bloody genes to actually make these organisms if we had gone with what had been the assumption to that point, that one gene makes one protein and that’s it. So you have a gene for making a thing and, if an organism has a million different things that are required, a million different little special Lego bricks, if you will, required to make it functional then there has to be a million genes behind that. What we were finding was fewer genes than there ended up being types of proteins in organisms, by our best estimate. That was a bit of a shock, obviously. What that suggested then was there was some other level of data processing or data compression beyond just the gene. In other words, a single gene must then be able to code for more than one protein, in a sense. And that’s actually what we find is that even once a gene is transcribed, in other words, it’s read off to a piece of RNA that is then to go outside the nucleus of the cell and end up being turned into a protein that it can still be modified after it’s been read off the gene. In fact, it can be what’s called “post-transcriptionally” modified in many different ways. In other words, we found genes now that can be read a whole bunch of different ways. There’s a gene in fruit flies that we found, for example, that has all of these, what are called, “alternate splice sites” to it, so a single gene can be cut at various points. So imagine it as a single word, if you will, that could have sort of prefixes and suffixes or whatever, cut off of it and end up making different words. But this is a single gene that actually can make ten of thousands of different potential variant proteins, depending on how it’s spliced. We’ve just come to realize that a single gene may actually be capable of making thousands of different, slight variant proteins, depending on how they’re being regulated after the gene is transcribed. What that means is that what’s happening after a gene is being read involves all this other subtle regulation. And we’re just now realizing just how prevalent that is to making organisms. So there is again all these other levels we have to address.
Marcus: I’m happy with this fact. It means not only job security, for me personally, but it means, when I get up in front of a class and I tell students this, I can say, there’s much work to be done for those of you who find this interesting. We need more people getting involved. There’s much more to do.
Blake: That’s good.
Marcus: I think so.
Blake: How do scientists feel about the amount of public policy that governs what they can do in the lab?
Marcus: That’s a good question. You might imagine the view that might get portrayed in movies or mad scientists, like in Futurama, that scientists are always trying to find someway of getting around those damn stuff-shirt officials that are stifling their research. But it’s often the scientists that are leading the charge and trying to inform policy makers and their constituents, first, of course, on the benefits of doing research on things such as stem cells, obviously; we want to be advocates for why the work we do is important. And what that means is the good scientists need to not just look at it in terms of, well, my research is important because it’s interesting, but to justify it and to say, well, here’s why it’s important, here’s why it’s important for human health, for conservation efforts, for whatever reason your science may be important; you need justify it and plug it into everyone else’s everyday life. I think you will also find that scientists are often involved in trying to lead the charge in the debates for say, for example, ethical standards. We’re actually pushing for ethical standards and for building up those mechanisms for oversight of research and things such as animal welfare. I’m involved in my university’s building of our animal care infrastructure. I should be; I’m one of the people intimately associated with the use of animals and I want to be involved in making sure that we do it right. Speaking from my own perspective, I look around at my fellow colleagues everywhere and we’re the ones who know how things work and we want to be there to actually make sure it’s done right. So I don’t look at policy as necessarily a stifling thing. I look at it in terms of, you know, there need to be ethical standards and, if we want to insure that there’s rules and regulations and that they don’t also limit opportunities to get research done, then I want to have a hand in it, so that I can foster research, but at the same time, insure we do it in a fair and ethical way.
Ben: What do you think about the patenting of life forms? I’ve been reading some stuff lately, in fact, there was a piece on 60 Minutes last week that was talking about the ways in which genes and other things like that, depending on how the courts rule, either can or can’t be patented. What are your thoughts on that?
Marcus: I don’t know personally where I stand on that yet. From one side, I can see the necessity, especially if you have a research group and researchers that has put a lot of sweat equity into developing a set of techniques; they’ve built a special transgenic animal and they want to make sure they get some say in how research progresses in that area. I struggle with this in my own ways all the time in that I want to make sure that I don’t get run over and did I protect my own interests. But at the same time, the whole idea of science is that we don’t say, here’s my hypothesis and then hold it close to your chest, but that it becomes common domain. The things we discover are common domain and that we say, here’s my hypothesis, you publish it, and then you step away from it. It’s not really yours anymore. From a purist’s standpoint, I feel that, well, you’ve developed an organism that may be useful scientifically, but to limit who has access to it is a worrisome thing. But at the same time, I can say, well, a lot of people’s livelihood may be involved in this. There’s various categories of this, too, because one thing you’re going to find is a lot of, for example, commercial patenting of microorganisms that are going to be involved in such thing as bio-remediation; we keep dumping oil spills and other sorts of hazardous things on the planet, you’re going to find more commercial ventures that are going to rise up and clean up messes and they’re going to do this probably through the use of bio-engineered bacteria that can scrub out toxin or oils and convert them into something happy like, I don’t know, marshmallows or whatever they’ve decided to engineer. Those are going to be patented organisms. It’s a conundrum.
Ben: Would there be a difference between whether the research would be publicly funded such as through CDC or whether it’s Merck or something else?
Marcus: Yeah, I think that’s going to be the big difference; it’s going to fall into two categories. If there’s a pharmaceutical company behind the funding for a particular microorganism or some sort of commercial venture that’s not actually medically oriented, but, say, it’s in bio-remediation or restoration ecology or something like, that’s where you’re going to see a lot of patenting and you can expect to see that and limited or locked access to those organisms; there going to become proprietary and people are going to get sued for trying to build an organism that’s close to it or stealing or all of these sorts of things. If it’s someone whose doing research that’s funded, say, by the National Institutes of Health or the National Science Foundation, which, of course, are government agencies that fund much of the basic science that’s done in this country and, say, we have a group that has designed a special knock out mouse and they attempt to patent it, I think you’re going to find a much more liberal and open access to that organism and that the patent may be there to, in some way, protect some intellectual property rights, but not in a way that makes it completely proprietary. There’s already some of this in some ways. If you develop, say, for example, you produce an antibody in an organism and you spent a long time to do that, you have some control over who has access to that; other researchers have to contact you to get a sample of it for use. It doesn’t mean you won’t let them have it, if they request it, but it does let you sort of have some control over who gets it and when.
Blake: Interesting. I think as in some of the same ways as software, more specifically in publishing, people want to heavily control software development and patent software, but software is easily replicable. For drug manufacturers to do something like create a bacteria or virus that can code for a protein to help suppress cancer or something like that, it’s not like a drug in the sense they used to make drugs because this drug reproduces itself because it’s made of life and that’s what life does, right?
Marcus: And your patent is always changing on you, too.
Blake: Right. It will evolve. Pretty tricky.
Marcus: This will be an interesting thing to bring up. This might make patent lawyers’ head explode; you might have send patent lawyers…law school might require you to take an evolutionary biology class at some point. That would be hilarious; I’d happily teach that just for the amusement factor. At what point does your patent evolve outside of the defined patent that you laid down for it? If you patent something, you have to define it and describe how it is different from the other things. If it evolves on you over time, at what point has it evolved beyond the patent and so people aren’t actually infringing on your copyright if they have access to it. Couldn’t you simply steal one of Merck’s bio-remediation bugs and add a couple of extra genes in it and, say, well, it’s evolved, it’s not the same one. I’m sure these are going to be court cases at some point.
Blake: I do want to specify we’re talking about patents and not copyright, specifically because of my bringing in publishing. I specifically mean, in the software world, they want to patent these things, which are easily “copied” that have nothing to do with copyright. The same sort of evolutionary things can have to do with software; it can evolve, as well. Patenting software, I think, is a bad idea, but that’s just my opinion. I think maybe within the realm of patenting life forms, and this show is not about politics, but the legal ramifications of patenting life, or segments of life, are going to be really hard to unravel.
Marcus: Well, one way to think about in a much broader sense beyond just say organisms and software, is to remember that the history of information is always about the continued decentralization of information. Once it starts to become common access, it’s very hard to make it proprietary and locked up. Organisms are ultimately genomes, they’re information content, and once that becomes available, it’s very hard to make it unavailable to people again. You can go on-line; you don’t even have to have access through a university anymore, and look at genes and genomes for organisms now. That will just become more and more common. I don’t know how it’s going to be possible to keep people totally hands-off of a particular genome. I’m just not sure how that’s going to work.
Blake: You were involved in the Tiktaalik dig, so there’s a paleontology aspect to your job, as well as an embryological aspect. How do you like to split your time? Where do you find most joy in your job?
Marcus: I love doing the fieldwork, but fieldwork is a rare, few and far between thing. It’s expensive and it’s always a gamble because you’re saying, well, I’m going to go out and find something someone hasn’t found and I think I can find it in this place, so it’s a needle-in-a-haystack venture and those things are hard to find funding for.
Blake: There’s a huge amount of variation morphologically between an embryological specimen and a full adult, so don’t you lose a lot of that knowledge when you have to terminate these embryos early on?
Marcus: To some degree that is the case. As with anything, you’ve got to do things comparatively. If you only have a single data point, you can draw any line with any slope you want through that and so you’ve got to bracket off of as many data points as you can. Let’s say that I learn something about how a gene works by only looking embryos that are only viable up to a certain point; I have to put them out of their misery, if you will, very early before their little bits of cartilage actually will form into the adult skeletons. What that means is, I can’t see what the effect of that gene being knocked out would be on the adult form, maybe because there would be no way to make an adult form, even if I didn’t have some set of ethical standards or regulations over me. What I’ve got to do is I’ve got to turn to the other types of data. One is the natural variation that exists in the adults normally for that species. What kind of variations you see in the skeleton across the adult, the natural variation, then I can broaden that out further still and say, what variation do I see among similar species, then I can broaden that further out and say, among species and fossil ancestors. What we can do from that is we start to get a metric, sort of a playing field, of what skeletons can and can’t do, then we can go back and test against those genes. We can ultimately sort of extrapolate about what those genes are doing by knowing the limitations of what adult skeletons can do over long time series from the fossil record, from the living variation among animals today, and then from the perturbations we get from the embryos. No one line of evidence, by itself, is damning, if you will, for answering a set of questions. But when you line up perturbations in embryos, natural existing variation in living populations, and the data set over potentially hundreds of millions of years in fossils, you get an emergent picture. At least you hope you do.
Karen: Marcus, we’ve got an obligatory question that we ask all our guests, what’s your favorite monster?
Marcus: My favorite monster. Well, I’m going to default to my favorite vertebrate, sort of my mascot vertebrate, if you will. It is my favorite vertebrate; it is also my favorite fish using the proper phylogenetic term, proper usage of fish, not the word we use for fish on an everyday basis, but what we use as fish when we’re building evolutionary trees. It also happens to be my favorite dinosaur. It is also my favorite organism at my backyard birdfeeder. It’s the tufted titmouse: baeolophus bicolor. It’s a little small gregarious gray bird with a little bit of a Mohawk. They generally pair bond and will form a bond at least through a single breeding season; they like to swoop down on large mammals and pull fur out of their backs to built their nests. They’re angry little adaptable birds, extremely intelligent, extremely successful. They’ve dealt well on the margins of human encroachment; a perfect example, I think, of a clever, but alien, to us, at least, vertebrate dinosaur on many levels and, I think, just a rather handsome example of an animal. If Carl Sagan had consulted with me back before probes were sent out of the solar system with the engraved examples of naked humans on the side of our Voyager space probes and instructions on where to go and find those naked humans if an alien were to come across that ship, I would have also engraved the little tufted titmouse on there just for good measure.
Karen: I was going to say that’s not a prototypical monster. I thought you were going to say Bigfoot.
Marcus: Bigfoot! No, no. Show me the data.
Blake: I like it. I like it. Well, thank you so much for your time.
Marcus: Thanks for having me. I enjoyed the conversation.
The views expressed on this program are not necessarily the views of the Skeptics Society or Skeptic magazine.
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