Allan Spradling talks with StemBook about polyploidy, evolution, and the state of funding for basic science

Allan Spradling is a Staff Member and Director of the Carnegie Institution Department of Embryology and an Investigator of the Howard Hughes Medical Institute. Additionally, he is an Adjunct Professor at Johns Hopkins University. Allan and his laboratory study drosophila oogenesis, and more recently the intestine, in order to explore a range of questions including differentiation, the niche, and aging. Allan recently spoke with StemBook editor, Lisa Girard.

Allan, thanks a lot for talking to StemBook. I was wondering if you could tell me about some of the current projects that are going on in your lab?

 My lab has a lot of very diverse projects. You have probably seen that many of my papers just have two authors. Everybody does something a little different, they can take it with them, and that’s the style of the lab.

 So, let me just tell you a few things in stem cell biology that we are very interested in, because we work in some other areas also. Recently, we finished a study of the drosophila small intestine, the midgut, which showed that it contains not a uniform population of stem cells, but has slightly different stem cells in multiple distinct sub-regions. The different sub-regions of the intestine have different stem cells in the sense that they can’t substitute for each other. What we are thinking is that all the big tissues of our body; our intestine, our skin, all of these stem cells, may be subtly different in different regions. They might be specialized for a different microbiome and for slightly different physiology. This situation would offer really interesting opportunities, but it would also mean that you can’t just make a generic type of tissue stem cell and expect it’s going to work everywhere. We tested this by marking stem cell clones and we could show that the stem cells from one region usually can’t make the cells in an adjacent region, even though you don’t see any real boundary until you look at the EM, gene expression, and things like that. I think this expands the sophistication of our view of these large tissues and their thousands of stem cells and reveals more extensive regulation and biology than was known previously. One of the cool things it suggests is that because these stem cells are much closer to each other than you know, stem cells from different tissues, just changing a few genes might turn one regional stem cell into another. For example, if you had to cut out a piece of someone’s intestine, we know that often has a lot of weird effects that are not really understood. We think it may be because each segment has these regional functions. You could reprogram the stem cells in another gut region or part of another region to become stem cells characteristic of the lost region.  Because these regions are always turning over, those changed stem cells would soon re-build a copy of the lost region in that location. So one might be able to do homeotic transformations in adults by reprogramming closely related stem cells and we’re kind of excited about that.  A graduate student, Alexis Marianes, did this work.

 Another thing, we’ve been looking at is the repair capability of fly tissues.  Vicki Losick, a postdoc in my lab, has found an alternative to our normal expectation of how wounds are repaired, which is that diploid cells, such as stem cells or progenitor cells that are arrested, will proliferate and repair the wound.  She found that two processes that generate large cells but do not involve cell division, namely syncytium formation and polyploidization, make big contributions to repairing wounds in Drosophila abdominal epithelial cells.  Polyploidization and fusion represent the major pathways for responding even when hundreds of cells are lost and we think that there are important reasons for this.  In these wounds a scab forms that actually stays permanently.  So you have a big extracellular structure and then the epithelial cells around it.   We think that by enlarging the cells have an easier time interacting mechanically with an extracellular large structure because large cells can generate big cytoskeletal fibers, just as myoblasts fuse to make a muscle cell. So, we suspect that in heart attack, in aging humans, and in a lot of tissues, big cells and syncytia form; but people may have largely ignored it. After a heart attack, or after a scab forms; what are the big cells actually doing? We are excited about how polyploidization and cell fusion are regulated and what sort of cell biology generates appropriate fibers that mechanically stabilize the tissue. We’ve studied polyploid cells in several contexts and we think they are exceptionally interesting cells. The reason being, once you get a few copies of the genome, you are much more free to play around with individual genes than you are as a diploid cell. You can’t afford to lose one gene copy in a diploid cell, but if you have 8 or 16 copies you can amplify, rearrange, do whatever you want with a few of them; you can even be aneuploid somewhat. We see this naturally in drosophila in the rectum. There, cells that are polyploid normally become aneuploid, as Don Fox discovered a few years ago.

 So, do you think it’s some kind of evolutionary mechanism?

 Yes, we are trying to understand the function and understand the mechanisms. I would just point out that mammalian cytotrophoblast, the maternal cells that help remodel the maternal circulation of the placenta as pregnancy goes on, become polyploid and aneuploid as they migrate and remodel both the placental vessels and the muscles of the uterus. People like Susan Fisher have done beautiful studies of that process. I’m really excited these mechanisms may be analogous to those of the Drosophila rectum.  Might similar things be happening in the brain? Is that happening in other places where you might want some extra somatic diversity created during development?

 The polyploid cells in drosophila have been well studied, what about in other organisms?

 Well, there are quite a few polyploid cells in mammals- megakaryocytes, named that for a reason, of course. It’s interesting that in almost every embryo the trophic tissue seems to become polyploid. We’re interested in what it is about trophic functions that makes polyploidy an advantage. When dealing with a large extracellular structure like a scab, maybe being big would be helpful for mechanical stability.   In providing trophic functions to an oocyte or an embryo; it may be easier to transport materials from a smaller number of giant cells rather than from a larger number of diploid cells   I tell people in my lab, “think of the absolutely most interesting explanation for your results and then you should rule that one out before you go to the second most interesting.” I suspect that genomes get modified more during development than people currently believe.   Polyploid cells should be good places to look for further examples.  My enthusiasm was generated early in my career when I found that the follicle cells of drosophila amplify their eggshell genes.  Well that’s something that evolved. Either this kind of thing happened just one time in all of biology or it is happening more commonly but is just not that easy to document.  I suspect there are many situations in which limited somatic genome modification is going on, but they just haven’t been discovered yet.

Do you see any kind of stress-induced polyploidy? For example, if you heat shock animals?

Well, in the abdominal wounding system or following damage to the hindgut, you definitely get a significant amount of polyploidy induced as a result. That’s one kind of stress. I think another interesting case is nutritional stress. Several people, including us, are working in the intestine-probably our second favorite tissue now. Normally, the enterocytes polyploidize a little bit downstream from the stem cell. However, following increases in nutrition or after tissue damage, you can get stem cell expansion, as well as increases in the level of polyploidy of the enterocytes. Similar changes might occur in response to various stresses such as infection, starvation, toxic food, damage, etc. From mutants we have known for years that if you reduce the normal number of nurse cells, which are polyploid, the individual cells that are left will get bigger to compensate.  They somehow know the final size needed as a group.  But that molecular mechanism that allows them to size regulate is not known. What are they measuring?  That’s really not known.  The same sort of regulation occurs in mammalian tissues as well. It would be interesting to learn if related mechanisms of size control are used in different groups. Is the system counting cells or sensing the total amount of DNA, or a diffusible product that’s being passed back and forth?

I know you have been involved outside of the lab in important capacities such as with the Society for Developmental Biology and the Genetics Society of America. I wanted to get your view, given how funding is changing for basic researchers, on what you see as some of the more positive trajectories that might emerge from how things are transitioning.

 Well, I think that first of all, science is not going away, I don’t see a reduction in the amount of money being spent on science.  Despite the present absurd situation, funding is likely to continue growing in the public and the private sectors, as well as the nonprofit sector on a world scale.  I think the careers are going to be there. Science is too valuable. You can argue it’s getting even more important in the global competition for economic development and innovation. The question is, whether our current system for getting people into science in a highly productive way is going to survive.  For years the U.S. system has fostered a high level of scientific productivity here, it has been our secret weapon. The secret has been to let young people become independent very early, almost earlier than anywhere else. But we’re losing that.  We need to identify good young people, give them money and let them do what they think is good. Then just judge them on what they’ve done, and give them more money as long as they continue to do well.  That’s been the secret of the American system. Writing a grant that sounds good on paper, that’s completely unimportant. It’s what you actually do; it’s the productivity, the innovativeness that matters. We need a system that rewards scientific discovery and productivity, like the older system used to, not promises and hype.  There are plenty of good people and there’s plenty of science to do, more than I’ve ever seen in the past. You just need a system that gets the money to the people that are itching and waiting to do innovative work rather than forcing them into standardized, mainstream, incremental projects, or worse.  Top down direction of research just doesn’t work very well in basic science. Today is no different than in the past. Every good idea starts with one individual. I definitely think that the voices of people working in model genetic organisms like the mouse and the fly need to be heard more clearly in setting research priorities .   There are a lot of disease oriented lobbies and congressman who are well meaning, but don’t understand what works in biomedical research.  But we seem to be evolving toward a system where the people that really know where science can go and where the best opportunities can be found are less and less influential. I think the scientific societies should band together and establish a mechanism to articulate for the public what actually works in research.  Society deserves to get the best possible value for its research investment.  Increasingly, this is not happening, as more money is invested in top down projects that underperform their promises and produce few insights.  We need to reinvest in what has made science great in the past which is investigator-initiated research that does not respond to any specific mandate and is justified by its inherent quality, not hypothetical disease relevance.