All right, should we get started? All right, well, it is my great pleasure to introduce this year's Steambach lecturer, Professor Michael Rosen. The Steambach Lectureship honors the legacy of Harry Steambach, whose pioneering work in metabolism identified vitamin D deficiency as the cause of rickets and represents the biochemistry department's most prestigious honor and recognition we bestow upon a scientist. Professor Rosen did his undergraduate studies at the University of Michigan, where he was selected as a Winston Churchill scholar to pursue post-bacc studies in Cambridge. He received his PhD at Harvard University in Stuart Shriver's Laboratory in 1993, where he did pioneering structural and biochemical work on immunofillings that clarified the molecular basis of these important receptor, ligand, receptor interaction pairs. As a postdoctoral scholar in Tony Pawson and Lewis Kay's laboratories at the University of Toronto, he developed novel techniques for studying large proteins by NMR and used these methods to investigate the structural basis of intramolecular interactions such as auto inhibition, which play a key mechanism in cell signaling logic. These studies telegraphed the broad direction of Professor Rosen's own independent research group, which seeks an understanding of the cell that bridges different length and time scales. His group's early body of work from Memorial Sloan Kettering provided an amazing view of how the nanoscale activities of signaling proteins can direct the microscale organization of act and polymerization within the cell. Professor Rosen moved to UT Southwestern in 2001 and was named an HHMI investigator in 2005. Since then, his group's continued investigation into the multivalent organization of signaling complexes led to the groundbreaking discovery of biomolecular condensates as major players in the organization of molecules within the cell. Since then, his group has produced a focused, elegant, and biochemically grounded understanding of the biophysical properties of these fundamental structures within the cell and has identified key ways in which they can be regulated to control important aspects of cell biology, ranging from chromatin structure to the cytoskeleton. In addition to their importance for basic science, Rosen is exploring translational applications targeting phase separation as a founding scientist of phase medicines, which has recently raised more than $80 million in capital. Professor Rosen has received countless honors and recognitions, including most recently the Wiley Prize and Kaiser Award, and he was recently elected to the National Academy of Sciences in 2020. And so without further ado, let's welcome Professor Rosen for the first of two exciting lectures on this exciting and groundbreaking work. Well, boy, thank you very much for that, that very kind, overly kind introduction. It really is a great pleasure here to give the Steenbach lectures. From what reading I've done about Harry Steenbach, he was one of the founders of the field of nutrition, which of course matured into or developed into the field of biochemistry, which is really where I'm grounded. Steenbach also was one of the early people who argued for the importance of commercialization as a way of taking basic science research and enabling it for the public good. And Warf here basically developed from his desire to take his understanding of vitamin D and production of vitamin D and enable at the time the cattle industry but also treatment of children with rickets. And as you just heard, one of my hopes is that we will be able to develop our understanding of, as you'll hear about, biological phase separation into new ways of developing therapeutics through phase medicines to cure things or at least help diseases including ALS and certain kinds of cancer. So again, it's wonderful to have the opportunity to spend a couple of days here with you in Dr. Steenbach's honor. So research in my lab for about the past dozen years or so has focused on, I can move beyond this, has focused on a family of cellular structures, cellular compartments that we term biomolecular condensates. These are compartments primarily in eukaryotic cells, probably also in prokaryotic cells that by definition concentrate molecules, certainly proteins, certainly RNAs, probably small molecules as well, in the absence of a surrounding membrane. So these are distinct but related in some functional ways to the canonical membrane-bound compartments, nuclei, mitochondria, Golgi, et cetera. They're sort of better understood and in textbooks. As I've tried to indicate here, what my lab has taken to calling the egg picture, there are many, many different kinds of biomolecular condensates throughout the cell and they are involved in a huge range of biological processes. Everything from signal transduction at membranes to the organization of RNA and metabolism of RNA and various compartments to certain aspects of gene expression. Over the years, condensates have also become associated with many different human diseases, most notably neurodegeneration, which results from mutations of certain proteins that are known to be resident in certain kinds of condensates, but also more recently it's become clear that defects in molecules resident in condensates lead to things like cancer and skin diseases and moreover that one can treat other kinds of diseases through targeting condensates involved in the relevant biology. So understanding condensates we think is going to be relevant both to understanding basic biological processes but also hopefully will provide, as I said, insights into creation of new kinds of medicines. A key feature of condensates is that their components are quite dynamic. They both move within the molecular molecules that are in them, move rapidly within them, but also exchange between the concentrated condensate structure and the surrounding cytoplasm or nucleoplasm. But yet somehow, although they are dynamic, they are distinct. So different components concentrate in different kinds of condensates which then endows them with different kinds of biochemical activities. And in general I think it's fair to say that these appear to function as kind of intermediates between macromolecules that are organized and function on nanometer length scales and canonical membrane bounded organelles that again are organized and function on micron length scales. Now when we first got interested in this area and it's been about a dozen years now, we set out a series of questions that we were hoping to answer over time. So first, what is the physical nature of these condensate structures? How is it that they're able to form and still exchange molecules with the surroundings but yet be persistent over time? Second, what is their chemical nature? What kinds of molecules make them and can we understand how they might be regulated and function according to that chemical composition? And again, closely related to that, how can they be regulated? Because no organization in biology means anything if cells can't control it. And then finally, perhaps most importantly, what are the biochemical and cellular functions that arise from a formation of these condensed structures and how do they arise from the physical properties, chemical composition and regulation? So what I'm gonna tell you about this afternoon is a series of stories. At the beginning, I'm gonna give kind of a historical introduction how we got involved in this work that will take us through essentially, I think key aspects of physical nature, chemical nature and regulation. And then I'm gonna move into some more recent work for my lab that gets into what I think is really this key issue in particular, what are the biochemical functions of condensates and what kind of biochemistry is arise uniquely from assembling molecules into these higher order structures? So I will begin, as you heard from Scott, with previous work in my lab before we stumbled into this area, focused on understanding structural and biochemical aspects of signaling pathways that control the actin cytoskeleton. And we were particularly interested in signaling pathways that controlled this actin nucleating machine called the ARP-23 complex, which had been discovered around 2000 by Tom Pollard's lab that binds to an existing actin filament and can grow a new actin filament from the side. And in that process, that nucleation of actin filaments, ARP-23 complex controls a vast array of cellular processes. Now, ARP-23 complexes are activated dominantly by proteins in the Wiscott-Aldrich syndrome protein family or the WASP family. And many of them, like this molecule, N-WASP, have long proline-rich regions. And so N-WASP is a molecule that has about 150 amino acids stretch in it that's sort of a long disordered loop. Fully half of the amino acids are proliens. And so there are many, many, roughly nine, as I've shown here, different binding sites for sarcomology three domains, SH3 domains, which I suspect virtually everybody here knows, is a widely expressed signaling module that binds to proline-rich peptides. Now, suffice to say, we published a paper in 2008 that suggested that oligomerization of N-WASP proteins should be a means of potentiating their activation of the ARP-23 complex. And so we started looking for molecules that we thought might engage this proline-rich element to cause oligomerization. And so in particular, we started studying a protein called NCK, which is, again, a widely expressed adapter protein that contains an SH2 domain, a sarcomology two domain that binds to proline-rich motifs, and contains three SH3 domains that are known to bind to, as I said, these proline-rich motifs. And in fact, a lot of studies before we got into this had shown that NCK binds to the proline-rich region of N-WASP and is involved in controlling N-WASP activity. And we kind of just looked at that and thought with our hands, well, if you've got something that has three, a SH3 domains on it, and you've got a ligand that has nine binding sites, that should be a system that can create oligomers. You have one NCK that might bind one N-WASP molecule, there'll be other sites that are open and another N-CK could bind and so forth, so you could get polymerization. And as I said, we published this paper in 2008 that showed that oligomerization would be a means of potentiating this activation pathway. And so we started fiddling around with these two proteins in the lab, and then one afternoon, my student, Wei Chen Cheng, basically had this weird observation. And that is, she showed that when you mixed NCK and N-WASP at low concentrations, not much interesting happened, but as you increase the concentrations of the two at some very sharp point, the solution went cloudy. And eventually, after a couple of days of trying to figure out what this cloudiness was, we put it under a microscope and we found that when you mix these two things together, you get these little liquid droplets. And we could watch them float around in solution, we could watch two of them come together and fuse into a larger droplet. So for example, this, if you can see there in the back, this sort of figure eight is almost certainly two droplets that are in the process of fusing when we snapped this image. And moreover, the proteins become hugely concentrated in these droplets. So if we label either of them with a floor or floor, we could get an image like this, which is matched to the bright field image there. And you can see that the green fluorescence, in this case, I believe, of n-wasp, is much, much higher than in the surrounding liquid. And approximately in this case, about a hundredfold increase in concentration in the droplets than in the surroundings. And we thought to ourselves, huh, you know, we thought we were just gonna make oligomers, tetramers, octomers maybe, but we've made this weird structure. And what could that mean? Well, of course, while we were doing all of this biophysics and structural biology in my lab, we were doing our best to follow the cell biological literature on these molecules. And what we knew is that a lot of people had shown that when proteins in this whisked altered syndrome protein family, this wasp family, when those molecules are used in cells, very often if you label them with floor floors, you can see they make these very bright foci. They get assembled into some kind of high concentration structure. And those structures, it's easier to see here with these invadipodia are sites at which actin is assembled to cause changes in cell morphology and cell adhesion. And so we thought, well, you know, we have this unusual process of forming these liquids of this phase separation that concentrates molecules. Maybe this process is what's going on here in cells. Could this be a mechanism to explain that process? And so we started to think, you know, how could all of this occur? And eventually we made a connection to polymer physics and polymer chemistry that I think has really given us a very strong grounding into how some of these cellular structures may form. And this literally dates back to polymer chemistry, actually from steam box time. This is polymer chemistry that was Paul Flory, Walter Stockmeyer back in the early 1940s, you know, after some of steam box major discoveries, but still coincident with his time here. Because those pioneers in polymer chemistry asked the following question. They said, if I had some binary interaction to make a complex. And at the time they were starting the reactions of alcohols with carboxylic acids to make ester bonds. But all of the theory they developed, all of their experiments could absolutely be generalized. So here, you know, red circle interacts with a green circle to make two concentric circles would fit their theory. They asked what happens if those interacting entities are presented in multivalent arrays. So for example, if we have a trivalent version of the red guy and a divalent version of the green guy. And what they found, both with elegant quantitative experiments, but also really beautiful analytical theory, is that molecules of this ilk undergo what are called sol-gel phase transitions. Now, the name they chose for these was terrible because one is really not looking at a transition from a soluble thing to a gelatinous thing. This is a connectivity transition. That's important for people to understand the difference. What they found was, at low fractional binding or in a non-covalent system, as I'm trying to indicate here with concentrations on the two axes, at low concentrations, these molecules will assemble into small complexes, dimers, trimmers, tetramers, but basically small oligomers. And back in the systems they were looking at, those were soluble in solution, so they called this the sol phase. But as one increases fractional binding or increases concentration, there's a very sharp line beyond which these molecules will assemble into huge macroscopic polymers. And in the day, the polymers they were looking at were gelatinous in solution, so they called this a sol-gel transition, but as I said, it is in fact a connectivity transition from small oligomers to huge polymers. So anybody who's ever poured in acrylamide gel, basically you start monocrylamide and bisacrylamide and you start them polymerizing, you're making polymer chains that are gradually cross-linking, the solution gets more and more viscous and then instantaneously, if you don't pour it into the caster fast enough, the whole thing solidifies into one gel. You just did a sol-gel transition. Okay, so I think people can sort of relate to that. And again, they were looking at acids and alcohols making polyester, but all of this conceptually should hold every bit for proteins or macromolecules as well. Now, what they also developed, a little bit later in the 1940s, was an idea about solubility of these systems. And the idea as follows, the key concept rather is that as polymers get longer, they become less soluble in solution. And so if you have an eppendorf here with a solution of monomers in it, a little meniscus at the top, as those monomers start to polymerize, assemble into larger oligomers, they become less soluble. And eventually there's some critical length that's achieved that decreases the solubility to the point where they crash out into a separate phase. And since polymers are dynamic molecules, that phase tends to be a separate liquid phase. Now, for a non-covalent system, these two processes are thermodynamically coupled, such that if one starts with, let's say, some concentration of the red molecule here in solution and one titrates in the green molecule, as you add more and more green and move off to the right, the complexes that one makes become larger and larger. And at some point out here, they can reach the limit of their solubility too long to still be fully soluble in solution. And they crash into a second phase and they become highly concentrated in that phase. And so within that phase, they can jump into this regime so that now they've undergone a sol-gel transition in addition to a solubility transition. And I hope that this is clear to people. I've always found it to be sort of beautiful physical chemistry. And so the basic idea is that multivalent interactions can drive polymerization, move you across this plot to the left. And that, as oligomerization increases, solubility inherently drops. And at some point, one can then undergo phase separation to produce a separate concentrated phase and within that phase, you can move into the gel regime. And again, all of this was beautifully worked out all the way back in the 1940s. What they didn't know back then is that proteins consisted of multiple modular domains and that proteins might be able to do this. But when we made this connection, we started to think, maybe this is what's going on. Certainly, this is likely what's going on in our test tube and perhaps this could explain what's going on in cells as well. Now, science benefits tremendously from serendipity. So just a few months after we had these initial discoveries, there was what's now viewed as absolutely seminal paper in this field by Cliff Brangwin, who was in a postdoc in Tony Hyman's lab. So Brangwin and Hyman really get tremendous credit for this. They were looking inside C. elegans' oocytes and found that P granules, which was a compartment that was known, a member in this compartment at the time was known, they found that those behaved as liquid droplets. So for example, they could see cycles of fusion and fission when two P granules hit each other. They fused into a larger one. If they applied force to the cell, they could see some of them get pulled apart and separated. If they applied shear force in a particular direction, they could see a P granule kind of smear out in the direction of the force. And when the force was removed, they would round back up again very much the way liquids should behave inside the cell. And they could see rapid exchange of these components with the surroundings by photobleaching, all consistent with liquid-like structure of these P granules. In addition, the assembly and disassembly processes were suggestive of a critical concentration, sort of sharp line between one phase and two phases that I indicated previously. And so what they proposed is that P granules in the C. elegans embryo basically behave as base-separated liquid droplets. And they showed similar behavior just a couple of years later for the nucleolus in Xenopus suicides. And so when we saw actually the first of these two papers, we asked ourselves, well, what are the molecules within these structures? And I literally didn't even know these things existed before then to show my level of naivete. But sure enough, when we looked in them, what we found is that they are highly enriched in multivalent macromolecules. So for example, molecules that contain multiple RNA binding domains that can interact with repetitive elements of RNA. Many of them also contain so-called low-complexity sequences or amino acid sequences that are enriched in small numbers of different types of amino acids. And those can be, as I'll say more in a second, weakly adhesive. Moreover, I knew from my time in Tony Pawson's lab as a postdoc that there are lots of signaling molecules that are composed of repetitive modular domains. And so when we saw the Branglorn-Heimann paper and integrated it with our work, we really started to think, well, perhaps this process of phase separation doesn't explain just these actin-based structures, but perhaps many of these other kinds of structures, and perhaps many of these higher order things and cells writ large. And so that then led us to this model that we published in our first paper in this area in 2012, where essentially it is concomitant assembly and phase separation of multivalent molecules that could perhaps underlie formation of these, again, structures that we now call biomolecular condensates. Again, just two generic molecules here that are multivalent can interact and form essentially an oligomeric, polymeric network with decreased solubility and therefore a separate phase. Now, since that time, there have been lots and lots and lots of instantiations of multivalency-driven phase separation. So we've done a fair bit of work with multi-domain proteins, both engineered proteins, where we take a single domain and make repetitive versions of it, but also natural proteins that I'll say a lot more about that control the actin cytoskeleton. Other people, for example, Min-Ji Jung in Hong Kong has looked at the protein components of the postsynaptic density, which, again, are it's a whole collection of multivalent macromolecules that interact and shown that they can assemble and phase separate. There's been a tremendous amount of work done on these so-called intrinsically disordered regions of molecules, these polypeptides that don't adopt a discrete three-dimensional structure. And many of these have been shown to phase separate through a variety of different kinds of weakly adhesive interactions, cation pi interactions, charge-charge interactions. My colleague, Steve McKnight at UT Southwestern, has done beautiful work showing that some of these disordered regions can form short so-called cross-beta structures that, again, can occur in multivalent fashion down a disordered chain. And we think all of these are, in many ways, analogous to what's going on with these multi-domain proteins.  Just in this case, the interactions are of higher affinity involved, discrete binding elements. Here, these are much smaller, weaker interactions, but nevertheless, multivalency is sort of the essence. RNA and DNA through repetitive base pairing elements will also undergo this process of phase separation. A point that's going to turn out to be relevant to my seminar tomorrow is that polymer chemistry tells us, actually, I would say soft matter physics in general, tells us that all of these ideas about multivalency-driven phase separation are completely independent of scale. And so a real neat piece of work came out of Pietro Di Camilli's lab at Yale, where he showed that synaptic vesicles, which are, of course, way, way, way bigger than any of these molecules here, that if you coat synaptic vesicles with multiple, weakly adhesive molecules, they will assemble and produce a liquid phase where you see dynamics and you see exchange. But the basic component of it is a vesicle, something much, much bigger than these. But the basic underlying concept is really the same. And that becomes relevant again to my seminar tomorrow, where I'll talk about chromatin through this lens. Now, one of the very nice things is because there's 80 years of polymer chemistry behind all of these ideas, one can turn to polymer chemistry to think about things like regulation. And so what polymer chemistry told us is that higher valence, the larger the number of adhesive elements in a given molecule, higher valence or higher affinity between the individual elements will promote ligamentization. I think that should be hopefully intuitive. And thus, they will promote phase separation. And so it immediately suggests that if biology could control the valence of the interactions, biology could control this process. And so we've shown that that is indeed the case with this system that, again, I'm going to increasingly say more about. This is this NCK molecule with the 3SH3 domains and the NWAS molecule with the 9 proline rich motifs. In this case, these two molecules, when you mix them together, will phase separate. I showed you droplets from that. But you've got to go to pretty high concentrations. You've got to go to sort of double-digit micromolar concentrations, which is above biological relevance here. But so you can imagine at sort of meaning biologically meaningful concentrations, one could be below that phase boundary. However, NCK is a molecule that has an SH2 domain that binds to phosphatiricines. And what was kind of cool is that when we looked at all of the known NCK binding proteins, over half of them had three or more phosphatiricines that bound NCK. And so when you array NCK, then, on this scaffold, you have bumped up the valence of the SH3 domains, in this case, from three SH3s to nine SH3s. That shifts the phase boundary down such that concentrations that didn't phase separate here now do phase separate. And so the actions of kinases and phosphatases, which put on phosphates and take them off, could then be used by the cell to control where the phase boundary is and thus control whether the system's in a one phase regime or a two phase regime. We have a lot of data there showing those ideas. Moreover, there are many, many different covalent modifications of intrinsically disordered regions that can be used to increase or decrease the affinity of interactions between molecules. And those have been shown, I won't run you through the specifics, but those have been shown to either favor phase separation or disfavor phase separation. Moreover, again, all of this beautiful work from decades old polymer chemistry also can lead us to models that explain the composition of these structures. And so we put forward an initial very, very simplistic model in 2016 where we grossly divided the components of a bona fide cellular condensate into two groups of molecules called scaffold molecules were the ones that were highly valent whose interactions would give assembly and concomitant phase separation. And then, in other words, these are the molecules that create the structure. And so what one can see in terms of genetic experiments, these are the molecules that if you delete them, this higher order assembly goes away in the cell. In addition though, there are a lot of molecules that we know are concentrated in different condensates that are of low valency. And those get enriched in the condensate either because they can directly bind to the condensate of the scaffold. So for example, this one here, the green and the red molecule can bind, for example, or say the green and yellow molecule can bind to one of the blue sites in the scaffold. You can also have client molecules that bind to sites that are not involved in assembling the structure itself. I'd imagine those have, the condensate responds differently to high concentrations of the two of them. Also what we're finding is that there are molecules that can get into a condensate simply because they are physically compatible with the physical properties of the phase. And I'm deliberately vague on exactly what that means. All we know at this point is when we've looked at groups of small molecules, there are many small molecules that will enrich and vitro in a phase-separated condensate that don't have obvious binding sites on any of the components in there. So we think it's gotta be something about just the physical chemical properties of that condensed structure that's more favorable to some compounds than others. And again, we're trying to figure all this out now. What we have come to understand though over time is that this notion of scaffolding client and the distinction between them is absolutely not binary. We even intuited that earlier and that is more precisely one should talk about molecules that contribute to different degrees to forming the structure. So we now think about these as more scaffold-like. But you can imagine you could start with let's say a pentavalent blue protein and say what happens to the tetravalent, to the divalent, one can convert things from contributing strongly to contributing weakly. And so it's probably more correct to think about things as being more scaffold-like or more client-like, but this notion of a binary distinction is certainly not right. Not right exactly. And moreover, one shouldn't think about these in universal terms. In other words, a molecule that can be a scaffold under some conditions could turn out to be a client in others. For example, in the presence of high concentrations of this small client, the blue sites can be sucked up and not able to interact with the multivalent yellow molecule as well. And so under those kinds of conditions, the multivalent blue protein would behave more like a client and less like a scaffold because of the competitors. So again, one has to think pretty carefully when one analyzes, for example, biological data where condensates contain many, many dozens of molecules and the effects of perturbations. Moreover, it's important to note that these are very complex fluids. So the analogies that truthfully people like me and others in the field have made are like, oh, this is like oil and water. That's pretty good to explain to the person sitting next to be on an airplane who happens to be a lawyer or something. But to scientists, the oil and water analogy is a terrible analogy in that oil is a very simple fluid and the oil droplets in your salad dressing are homogeneous. These are absolutely, these are, in fact, we're finding more and more not homogeneous, they're heterogeneous at small length scales. And moreover, the different molecules that are within them behave very differently. Scaffolds are connected to other molecules through multiple binding sites. Clients, it's only a single binding site or a small number of binding sites. So their dynamic behaviors and their responses to change in viscosity, for example, will be different between different molecules. And so one has to pay pretty close attention when one makes perturbations to what kind of a molecule are you perturbing and what role does it play in creating the structure if you really want to interpret it. And I think that's something that's becoming more and more obvious as people study more of the biological systems and get away from sort of more of these toy systems that so many of us, including me, have been studying for a while. So with all of that as kind of introduction and background to the field, hopefully framing the problem both for today and for tomorrow, I want to spend the rest of my time talking about sort of that fourth issue on my initial slide and that is what a condensate to do, right? And that is what biochemical functions specifically arise from phase separation, right? Not just this condensate, must be important in signaling because it concentrates the kinase, but like what happens within that structure that makes the kinase somehow different? Is there anything that is different? And a core layer of that is are there any unique modes of regulation that are enabled specifically by the properties of these phase separated structures? And so I'll tell you sort of a longer vignette and then a shorter vignette to get at these next set of questions. So this takes me back to that pathway that I've been talking about on and off here. It's a pathway that controls actin assembly and the putacyte cells of the kidney starts from a single-pass transmembrane receptor called nephrin. That's a huge extracellular domain I'm not showing. Single-pass transmembrane helix and then disordered cytoplasmic tail that's phosphorylated at three sites that bind to the SH2 domain of NCK. And NCK is this adapter protein with three SH3 domains that then bind to the nine proline rich motifs in this n-wasp protein. And what my postdoctoral advisor, Tony Pawson, had shown is that when nephrin is assembled, concentrated at the surface of cells, these punctiform and they basically assemble very potently long actin tails from them. And since n-wasp activates the ARP23 complex to make actin film, it's basically, this is a system to look at how signaling pathways can control the ARP23 complex. And of course just looking at these at the outset, this seemed to us like a system that would phase separate. And so sure enough, if you mix these three proteins in solution, you can robustly induce phase separation. Moreover, if we attach nephrin to a supported lipid bilayer, so a lipid bilayer attached to a glass slide, if we uniformly distributes, but if we add NCK and n-wasp to it, it assembles into these micron scale clusters that have properties very, very much similar to these three-dimensional liquid droplets that we see when everything's in solution. And moreover, if we target nephrin to the plasma membrane of the HeLa cell and trigger its phosphorylation, we very rapidly see analogous punctate structures form that contain both NCK and n-wasp and assemble actin filaments. Now we could study actin assembly in this system by again putting nephrin, NCK and n-wasp on a supported, sorry, by putting nephrin on a supported lipid bilayer, adding NCK and n-wasp to it, and we can see formation of these micron scale puncta. If we add actin and the ARP23 complex to it, what we can see is that the actin rapidly assembles on the membrane and moreover, it assembles essentially always, at least as far as we can see here, on the puncta. And so the question is, why is it that actin preferentially assembles on the clusters? And there's kind of two potential answers. And one of them is sort of, well, duh, that's where the signaling molecules go. Of course that's where the actin assembles. But the other one is more interesting, and that is perhaps within the condensate structure, there's some change in the specific activity of these molecules that enhances their activity toward the ARP23 complex. And so a way to distinguish these would be sort of the following thought experiment. Let's say we have a membrane here that has these dots are supposed to represent individual, let's say, NWAS molecules. And we have a condensed region here that has, we'll say four molecules, but again, the condensates we're forming have hundreds and hundreds, but let's say we have one that's small that has four molecules here. And we have another region in the membrane that's sort of the surroundings, and let's say that has only one molecule. And we can then measure the actin assembly activity here and here, and maybe what we would see is that in the condensate it's higher and in the surrounding membrane it's lower, be consistent with previous data I showed you. Then if we normalize by the number of molecules there, the number of NWAS molecules there, we can distinguish these two mechanistic possibilities because if the reason there's higher activity in the condensate is just because there's four times as many molecules there, when we divide by four, the condensate activity should decrease and become identical to just the surrounding regions of the membrane. If however, something has changed, the specific activity of the molecules here are higher than here, even when we divide by the number of molecules we'll still have higher normalized activity than the surrounding membrane to a degree by which the specific activity has changed, right? Now, the way we're doing these experiments we can't measure number of molecules but we can use as a proxy fluorescence intensity. So if we normalize activity by fluorescence intensity we should be able to distinguish these two mechanistic possibilities. And my postdoc Lindsey Case was able to set up a very nice quantitative assay where again we can make clusters of this signaling system on a membrane, add actin in the arc-2-3 complex to it, see actin assemble, and then for any given spot in the membrane we can look at how rapidly actin assembled there. And so what we see is that inside a punctum we can see a rapid assembly and outside we can see much slower assembly. We can quantify this by looking at the maximum slope of these curves. And then the critical thing is we can take that slope and we can divide it by the local intensity of n-losp at that site, okay? So look at specific activity and even when we do that, so this is now normalized polymerization rate, we see that inside the condensate is appreciably faster than outside. So that means the activity per signaling molecule is higher inside than outside. So it's not just mass action, it's not just a concentration device. Something is different within the condensate. So the question is what? So I think we answered one question but then we set up, I think, an even more interesting mechanistic question, why does specific activity go up? So the first thing that we thought of was perhaps just there's some non-linearity in activity as a function of density. And I could explain afterwards why we thought that might be the case, completely wrong. Because we were able to attach n-losp to a supported bilayer just by itself and look as a function of density at this normalized polymerization rate, it's basically completely flat. And so it's not as though something about just the density of n-losp molecules gives non-linearity such that specific activity goes up at higher density. But we were lucky then to interact with Jay Groves, who's a single molecule microscopist at UC Berkeley. And Jay was studying very much an analogous system where he had a membrane protein called LAT that was phosphorylated on multiple sites. That interacts with a protein called GRAB2 with an SH2 domain, in this case two SH3 domains. And that interacts with a protein called SOS that has a proline matrix. It's an absolutely analogous to nephrin, NCK, n-losp, but just different set of molecules. And what Jay showed is that if you look at the dwell, the membrane dwell time, in this case of the SOS protein, if you looked outside the clusters, that membrane dwell time had a distribution. If you look at single molecules and their lifetime distribution, those molecules dissociate from the membrane very fast. Inside the clusters though, SOS has this long, long tail of increased dwell time out to tens of seconds. And that's because within the condensates there's higher connectivity than outside. And I'll show you data on this in a moment. Moreover, they developed a theory that suggested that increased dwell time could enhance or should enhance downstream signaling if the signaling is slow, multi-step and somehow driven out of equilibrium. This is classical kinetic proofreading. So what they argued is that this system is analogous to kinetic proofreading where dwell time here is analogous to the off-rate in systems like the ribosome. And so when we started to think about our system we realized it had all of the ingredients. Activation of the ARP2-3 complex is slow. It takes tens of seconds from binding of an ARP2-3 complex to creation of a daughter filament. There's a whole bunch of different conformational changes that have to occur and binding interactions that have to occur. And moreover, there's an irreversible step somewhere in this where ARP2-3 complex permanently latches on to the mother filament. In biology there are molecules that have to take that apart. But just in equilibrium it's irreversible. And so we thought maybe membrane dwell time could be the thing that would regulate this system. And sure enough, what we found across a variety of different perturbations is that, again, these are the data that I showed before. Inside has higher specific activity than outside in a condensate. And moreover, we always saw that the dwell time was higher in the condensate than in the surrounding regions and across a lot of different perturbations. And so basically paralleling the grove's idea of what we came to understand is that NWASP has to remain at the membrane long enough for ARP2-3 compass to go through all these steps and get turned on. And that if it falls off in the middle, the system has to reset back to the beginning. And that essentially is a recipe for dwell time dependence of flux through the pathway. Now, one of the neat experiments that my postdoc Lindsey Case did that supported this idea and also comes up with interesting regulatory concepts is the following. So she asks, what happens if I have a fixed density of nephrin on the membrane, a fixed amount of NWASP's solution, and I titrate in NCK? So if you walk through this, at low concentrations of NCK, any given NWASP molecule is gonna be attached to the membrane through nephrin through only a small number of bonds. And so dwell time should be short. At the other end, with a huge excess of NCK, any given NWASP molecule, yes, is bound to many different NCKs, but when there's an excess, only a small number of those are actually bound to nephrin and therefore bound to the membrane. So at this end, there'll be low membrane connectivity, again, dwell time should be short. In the middle, when the component concentrations are more balanced, any given NWASP is attached to multiple NCKs and they themselves are attached to nephrin in the membrane. So dwell time should be high here. And so we should see dwell time and maybe bell shaped activity. And sure enough, that's what Lindsay found. So again, fixed NWASP, fixed nephrin density on the bilayer and titrated in NCK. And you see that the dwell time basically goes up and then down as you go to excess and really strikingly, if you look at specific activity, specific activity goes up and then down. And Lindsay was able to do this and look at a correlation between dwell time and specific activity and boy, certainly there's a very strong correlation. I'm not gonna claim linearity because we don't have any kind of specific molecular model to explain this, but certainly there's a real strong correlation here. And she was able to do a series of different titrations and all of them basically can be aligned with each other correlating specific activity in membrane dwell time. And so we think this is a very strong argument for the fact that A, dwell time is really the key parameter. B, it also has, I think, a really interesting conceptual point to make about how activity can be controlled. Because normally when we think of controlling specific activity, we think about allosteric changes that change the inherent chemistry of a system. And this kind of a system where a condensate can form across a wide range of stoichiometries, simply changing the relative stoichiometries can change specific activities and thus change the signaling output from a system. And so we think it really, this is a new means of controlling protein activity that arises from these kinds of stoichiometrically undefined assemblies, whether they form through phase separation or not actually it doesn't matter at all, just they have to be able to form through a lot of different stoichiometries. This is something that we can observe actually in cells too. Lindsay rigged up a beautiful cellular assay where she can simultaneously image nephrin, NCK, n-wasp, as well as actin filaments. Just an example, here's a cell that contains these foci and there's one this punta that shows all three molecules in it. And again, she was able to photobleach these as a function with different NCK intensities and again see this bell-shaped fluorescence recovery. Also looked at actin intensity as a function of NCK and again it's bell-shaped and finally we can plot dynamics against actin intensity and we see again a reasonable correlation there. So both in vitro and in this cellular system, we think this idea that relative stoichiometry can control specific activity is going to be relevant. So we think that cells could use this as a way of fine-tuning a fundamentally switch-like system, in other words. One could imagine the cell in a single-phase regime and actin assembly activity is low. Signal comes in, causes assembly of the signaling molecules into a two-phase regime into clusters and then activity jumps up from here to here, but then within this two-phase regime, the cell could adjust the relative stoichiometries of the molecules or the degree of phosphorylation turns out to be functionally equivalent and then change activity within this sort of higher activity envelope. Of course, one could imagine cells needing to be able to make a switch-like decision but not wanting to give up complete control and this could be a way of controlling at the high end of the switch. So just to conclude this, we've shown that phase separation increases membrane dwell time and when downstream processes are slow and driven out of equilibrium, activity then will correlate with dwell time and because of stoichiometry's ability to control membrane connectivity, stoichiometry controls dwell time and thus stoichiometry controls activity, which is, we think, a new way of looking at control of signaling envelope. The last thing I'll note is that these behaviors are very likely quite general. There are lots of signaling systems that are composed of collections of multi-valent macromolecules. Many of them require activity through slow multi-step processes and so this should be something that's widely seen. In fact, Jay Groves showed exactly the same behavior in the paper that we ended up publishing back to back with the RASMAP kinase system, sort of the lat grab two sauce RASMAP kinase system I just mentioned before. So at least for an N of two, that's general. So I see that I have run out of time. I will not run you through the next vignette and you're gonna laugh a little bit that I thought I could get through all of this, but I'll make one quick point. We've looked at another system where we have recruited enzymes into a phase-separated compartment. Doesn't matter exactly what those are or what the compartment was. But in that case also, we have shown that condensates don't merely concentrate molecules, that there are changes in activity beyond that and in this other system, it turns out that within the condensate, the KM of the key reaction step decreases. And so we see higher activity, not just because the molecules are concentrated, not just because of mass action, but because of this change in KM. Now, we've only looked at these two systems in quantitative fashion. And in both cases, we found that the condensate doesn't merely assemble molecules, doesn't merely concentrate them, but actually changes elements of their reaction that further modulates activity. And given that sort of randomly chose these two, not quite randomly, but these are just two out of many, and we're not chosen for that specific effect, my bet is that this is quite general. That many different condensates that concentrate different enzyme activities, enzyme cascades are going to do things beyond merely bringing molecules together, that there will be elements that further enhance or further repress activity. And I think that's one of the real exciting challenges for those of us in the field to sort out. So I'll just finish to go back through those initial questions that I laid out. And lay out our idea that multivalency-driven phase separation, liquid-liquid phase separation, may drive the formation of some biomolecular condensates. An important point to make is that I don't want to claim that every dot you see in a cell gets formed this way. I think there's actually too much literature on that. Like, oh, we see a dot, it's formed by phase separation. Clearly, there are other ways of bringing molecules together and to foci you can see under a light microscope, by some smiles in the audience. I don't want to over claim this, but I do think that there's good evidence for at least a few of these that this process of multivalency-driven phase separation is relevant. And my guess is over time, as people study more and more of these in quantitative detail, some of them will look, oh yeah, that's the mechanism, and others will be, no, it's something different. But for those that do form through phase separation, I think we've gone a long way to answering these sort of initial questions that we laid out almost a dozen years ago. That is, what is their physical nature? Well, they are, again, for the ones that form this way, they are phase-separated polymers of multivalent proteins in their ligands. This would allow them to be both persistent, but also exchange molecules with their surroundings. What's their chemical nature? The composition can be controlled by interactions among scaffolding, client-like molecules, and therefore the interaction network between the various species within them. I showed you an important, we think, mechanism of regulation by changes in valency and affinity through covalent modifications, and there are many, many examples of this, both in vitro and in vivo now. And finally, one of the biochemical functions we're just, I think, beginning to scratch the surface here, but we've shown that reactions can be accelerated by mass action just by concentrating molecules, but also somehow modulated by various physical properties of the polymer matrix. And again, my bet is that turns out to be general as well. So I'll leave you with those ideas and just thank the wonderful collection of people I've had the good fortune of working with over the years. All of our initial work, sort of laying out some of these early concepts, came from a collection of really four graduate students in the lab. Salman Binani, Sadeep Manjade, Weichen Chang, and Pilong Li. Weichen and Pilong are now running their own laboratories and Sadeep and Salman are both postdocs and going on the job market now. The story of dwell time dependence was really exclusively done by a terrific postdoc, Lindsay Case, who just started her own lab at MIT about a year ago. The story I didn't make time to tell you about on the other enzyme system is a graduate student named Ben Keeples. I mentioned Jay Groves, who's a wonderful colleague and collaborator on all of this. There is the rest of my group earlier this spring as the mask mandates started to go down. We felt like we could get together at least outside. So I thank all of them for the really wonderful work in this area. And again, it's a real privilege to be here and to be able to give the Steenbach lectures and have the opportunity to interact with all of you. So thanks very much for your attention. I'll be happy to take any questions. Yeah. Good. How small do you think the collection of client molecules and scaffold molecules can be and still give the bend? Yeah, sorry. I wondered how small do you think the collection of scaffold molecules and client molecules can be to still give the benefit of phase separation in terms of dwell time? I mean, does it have to be tens of thousands of molecules or could it be a couple of dozen? Invite me back in a year. That's a terrific question. My background is structural biology. I think of tetramers and hexamers, right? And when do you go from a molecular system that properly should be understood through what we've all known in love as small discrete numbers of oligomers and at what size do you start seeing we'll say emergent properties? And I mean that in very specific terms. In this case, when does the dwell time go up? How big does it have to be? And this is a question that's relevant in lots of these systems. It comes up with transcription a lot. There's a lot of contention in transcription whether one should think about transcriptional foci as just a collection of a small number of molecules or sort of the phase separation thinking the better way to look at it. The answer is gonna turn out to depend on the specific nature of the system, the interactions between the molecules, the function that you care about. We are just starting to look at this with the actin system. We're making DNA origami of different sizes and putting nephrin on them and we will ask when does dwell time go up? But I think this is again, you've hit on sort of one of the forefront questions in the field which I think is great. We'll get to it eventually. I hope that long answer to a short question. So you presented this as a really fundamental process and I really liked that. It made me wonder about the evolution of this. Has anyone begun thinking how far back in the history of life do you begin seeing these types of concatenated domains and potential properties? Yeah, yeah, yeah. So people think about them in prokaryotes. Obviously the imaging gets harder as you get to something that's only two microns long. But there's certainly evidence of multivalent molecules in prokaryotes that will in vitro will phase separate or form higher order assemblies and form at one pole of the bacteria. So it seems like this is something that's very old. And in fact, if you look back in the physics literature, there were physicists who were arguing for phase separation as an important concentration mechanism back in the RNA world long before any of this sort of biological stuff really blew up over the last decade. So yeah, people are certainly thinking about it and the idea is that this may be beautiful for sure. Thank you so much. I was actually wondering is it possible to maybe capture like a structure? Because I know you said you had a structure background. Have you thought about trying to capture the structural like formation of how these coordinates look like? Because I'm assuming there's like some conformational change that occurs during this transition period. Yeah, come to my talk tomorrow, I'll show one image. We've begun looking at chromatin, kind of say phase separated chromatin and trying to understand the organization of nucleosomes within them. And it's really too early to answer your question, but short answer is yes. We're very, very interested in that. Polymer chemistry would predict that in order for a polymer to phase separate, it's gotta be in called a solvent regime where it collapses on itself at low concentrations. And what polymer chemistry predicts is when you get a lot of those collapse molecules together instead of being self-satisfied, they're satisfied interactions with others and they extend out. And so there's an anticipation that macromolecules, disordered chains at least, will be more compact outside of the condensate and more extended inside. But again, people need to do the analysis. Hi, great talk. Yeah, so I was curious about your metabolite kind of foray into that area. Do you have any clues about whether proteins that metabolize whatever you're detecting if they're nearby or if it's dependent on how concentrated the metabolite is in your system, whether you're seeing it in a condensate? And then I guess related to that, how do you even get a clean pull down or whatever of these condensates? Yeah, so you're asking about small molecule metabolites? Right. Yeah, so essentially, do we know this, if I understand correctly, do we understand anything about the small molecule composition? I guess the ones that you mentioned are appearing that you don't necessarily have any interactions with, with the... Oh, I see. The molecules that get in there without an obvious binding... Exactly, right, yeah. Yeah, so I'll tell you what we're doing. We're not doing that with natural condensates. We're doing that with synthetic, these engineered systems. And what we've done is we've added either a metabolite library, that we get from a metabolomics core facility, it's what they use to calibrate their instruments, or we've added an FDA approved drug library of about 1,200 compounds to them. And we've developed a mass spec assay that allows us to measure the partition coefficient. What's the concentration in the condensate and what's the concentration in the surrounding bulk? And what we found is that there's a surprisingly large number of compounds that enrich in the condensate and up to like 1,000 volts, so very high degrees. And when we've tried to use ITC to measure binding affinity between those compounds and the proteins that are in there, we don't see strong interactions. And so that's, I was deliberately vague on that. That's why we think it's probably some matching of gross physical properties of now thinking about this as a liquid droplet, rather than, oh, it's binding to something specifically there. But obviously those two effect, for a molecule that does bind, we think it will be both the physical properties and the direct binding that matter. And of course, you could imagine that biotech companies thinking about targeting condensates care a lot about that, so we're hopeful that we'll be able to sort of reveal physical principles of that eventually. Very cool, thank you. So maybe we just step, oh, was there one more? Oh, okay, sorry. Hi, so I had a question from what I got from this talk was that you made it seem that more so than the clustering effect, the biophysical properties created from the condensate is what causes change in like protein activity. So I thought toward bio-catalysis, if we understood what the biophysical properties of the condensate was, would it be possible to place these proteins directly in a solution that mimics those biophysical properties so that you're always actively getting the boost that the condensate provides without actually ever having to form the condensate? Yeah, we're hoping eventually we'll be able to get to that. So the idea is if we can figure out, for example, the compound that concentrates a thousandfold, if we can figure out what physical features of the droplet are the ones that allow it to concentrate in there so strongly, could we just make a solution that mimics those and if that concentration changed activity, would we see that change in activity? My guess is we are at least a PhD thesis or if not more away from having that understanding, but again, that's what I'm hoping to sort of the next period in my program. For sure, it's a great question. Hi, so when I look at these pictures of condensates, I always wonder what's in between them and how does what is in between them affect the activity within the condensate? So for example, if you generate a condensate in one cell type with the same molecules, will it behave the same if you generate it in another cell type that has a different kind of cytoplasm, say more ER versus, I don't know. Has anybody started playing those games? So people have done artificially. So Ned Wingrin and Zemriga Tai had a paper, actually a few years ago now, where they artificially created condensates by coupling, basically co-assembling two enzymes in a cascade and they were able to show and it was, so it was a branch point enzyme and two downstream enzymes that give different products and they showed that if they coupled these two together in a condensate that they could make essentially a functional oxytrofe for the other one. In other words, all the flux went down this pathway and none the other. The way they modeled it involved looking at diffusion of molecules from one condensate to the other. So the size of the condensate and the spatial distribution of the condensate and the flux through that compartment essentially outside of the compartment all played into the degree to which you got this arm going and not that arm going. Which is to say, yes, different cytoplasm or cytoplasm versus nucleoplasm, for example, with different components could make a difference. But to my knowledge, that's the only paper that's really looked at sort of those spatial issues. This is another kind of question. So if you were to take something like a P granule and put a metabolic enzyme into it, would the activity change? My bet is yes. We haven't done that yet. But in fact, we are reconstituting P bodies in vitro. And one of the things that we wanna look at is the activity of the P body components. But then the story that I didn't have time to show basically we rigged up an enzyme assimilation cascade to go inside a condensate. And the question is if you then took some exogenous enzyme or enzyme cascade, would it also change? We think that condensates tend to be more hydrophobic than the surrounding region. Because it is hydrophobic molecules that concentrate more strongly. And so reactions that respond to that, if they're in the condensate, could be accelerated that way. Again, these are on the docket of things to do. Interesting questions. Any more questions? All right, well maybe we should just continue the discussion outside for the reception.


All right, so first of all, I welcome you all to such a joint on behalf of the Economics Department, Tetsuya College, for joining this webinar on Career Opportunity in Economics. So first of all, let me just introduce myself. My name is Yumi Yannara Wozikam, and I'm a guest faculty in the Tetsuya College Economics Department, and I would just introduce you to our today's presenter, that is Ms. Lily Chishi, assistant professor, and then, of course, Dr. Devarvata, developing in charge, and then assistant professor. Okay, so before we move on, let me just give you a briefing on all throughout the today's program. So first of all, we will have a PPT presentation by our development in charge, that is Dr. Devarvata, and then he will take us through all this, the purpose of this webinar, and then after that, it will be followed by a short speech by Mr. Shakoy Konnyak, and then he will share with us all his experiences in the college, and of course, regarding the economics as a subject and what he in support the subject of economics, and which will be followed by a Q&A session from the audiences also, and all year, thousands of questions will be answered at the end of the program. So, we have Mr. Adho, I now give the time to serve Devarvata for his PPT presentation. Thank you, Mr. Yamyangar, for giving me the opportunity. Good afternoon, everyone. Good afternoon, sir. Welcome to today's session. Today, I will be talking about the career opportunities in economics, so economics as a discipline first of all, I will introduce the subject. What are the things we study under this particular subject? Then I will be talking about the job opportunities related, associated with this particular discipline. So, this is economics as a discipline. It is about 250 years old subject. And it falls within the paradigm of social science. The first book on this subject was written by Adam Smith in the year 1776, and then the name of the book was the Wealth of Nation. And this is the first book written documents we have on economics. As I told you, it is one of the oldest social science subject and it is the only subject among social sciences where Nobel Prize is awarded. So, what is this subject? This subject, economics, it is a study, this particular subject studies about production, distribution and consumption of wealth in the human society. It studies the behavior of the people, consumers, and how the individuals with a consumer make, be it consumer, producers, we make choice. So, it is a study which helps us to make the best utilization of available resources. Now, why to study economics? Firstly, it deals with scarcity. We all know that resources are scarce. This particular subject helps us to understand the concept of scarcity and how the valuable, limited resources can be used optimally. It helps us to make decision. This subject, the knowledge of this subject helps us to make best utilization of available resources. This subject also teaches how to predict about the future. We all know that our economy is a underdeveloped economy. We have about 20% or 20% people living below poverty line. The job of economists to frame policies and how we can solve this problem. So, the job of economist is to predict the unforeseen, maybe to design policies and by which we can have zero poverty in the country. It studies about choices and trade-offs. Next, I'll be talking about the different branches of economics as we all know that economics is broadly divided into two major branches. That is called microeconomics and macroeconomics. Most of us, we are introduced to these broad branches of economics in our 10 plus two economics subject. So, microeconomics, it is the study about consumer choice. How a consumer or a producer, takes decision. Microeconomics, on the other hand, it talks about national income. It talks about aggregate of economic phenomena. So, microeconomic studies, economic phenomena at a micro level. For example, how price is determined. This is a price is determined for a particular commodity. It is a subject matter of microeconomics. How price level is determined in the economy is a subject matter of macroeconomics. That's inflation is one of the parameters of macroeconomic concept. So does national income, et cetera. Next, we have other branches such as development economics, business economics. So, development economics focus on the development process of low-income countries. And primarily this particular branch of economics studies how we can reduce poverty, inequality, unemployment, et cetera. And there are so many theories that has been developed to study the development process of development and growth process of underdeveloped countries. Business economics, this particular branch is mostly taught to the students of commerce, BBA and MBA. So in this particular branch of economics, we study the application of economic theory and methodology to do business studies. Then we have branches such as environmental economics. It is concerned with the economic impact of environmental policies. We also have international economics and international economics is the study of economic interactions between countries and it addresses issues like international trade, investment, exchange of goods and services in Lementung, export and import of goods among countries. And then we have a specialized branch which is called econometrics. And in econometrics what we do, we use statistics, mathematics, models to verify economic theories. This particular branch of economics is used for custom. Then we have health economics. It is concerned with issues related to efficiency, effectiveness, value and behavior in the production and consumption of health and health sector. We also have health economics, public economics. In case of public economics, we study about government policies through the lenses of economic efficiency and equity. So public economic builds on the theory of welfare economics and is used as a tool to improve. Social welfare. The concepts that are studied within public economies, public economy is government budget, revenue, expenditure, taxation, et cetera. Next we will be talking about the skills that are required to pursue a career in economics. So to be a good economist, one need to possess good knowledge of mathematics. Economic theories are built on mathematical principles. So knowledge of mathematics helps us to understand the concept of economics much better. And yeah, much better. Next skills required to be a good economist is one should be aware of current affairs. It includes social, political issues and the mind to analyze these political, social phenomena. Then one should have inclusive mind. We should have research oriented and should have the ability to relate different aspects of the economy. Then we should have logical thinking. Apart from this, one need to have good communication skills, public speaking, to explain the complicated economic analysis to the general public and also to the people who doesn't know much of economics. Next I will be talking about these stages of higher education. Now, real economics wants to explain Now, real economics wants to, a student encounters real economy when he pursues a course in economic measure at graduation level. So real, the study of real economics begins at graduation level. So one can pursue BA economics or BSA economics. It is usually a three-year course in our country but some of the technical institutes in our country they run a four-year degree course as well such as IITs. Otherwise it is a three-year course and it is spread over six semesters. And in these six semesters as I told you about different branches of economics mostly these branches of economics are taught. Then one can pursue post-graduation, post-graduation it is a two-year degree, MA, MSc. Then we have one can go for research that is an ampoule. In some of the institute it is a one-year or it is a two-year course.  And then also if anybody is interested they can go for post-doctorate courses as well. So I told you I already explained about BA, BSA and the eligibility for pursuing BA and BSA in economics is class 12 and a student from mainstream can opt for this particular course. MA, MSc as I mentioned it is a two-year degree course and eligibility is BA, BSA in economics, ampoule. For ampoule one need to complete master degree and in some of the premier institute admission is done on the basis of entrance test. And if someone pursues ampoule course he is eligible for fellowship as well. Then we have PhD course as I mentioned it is a three- to five-year course full-time and eligibility is master degree or ampoule and to pursue this particular course government of India, MHRD and UGC they get fellowship and fellowship is quite handsome it's in some of the institute it is 31,000 per month. Then these are some of the premier institute in the country where one can pursue this MA, ampoule or PhD in economics. The premier one is Delhi School of Economics then we have Jawaharlal Neheru University we have ITIDR Mumbai, Jadapuri University, Hyderabad University Madras School of Economics, ISI, Indian Statistical Institute we have in Kolkata, Delhi and recently a branch is also operating from Teshpur University in North East, Assam North East and also we have IITs, some of the old IITs they are providing exceptional course in economics Kanpur, Kharagpur, IIT Bombay and then Madras and also IIT Guwahati and then other institution these are even Indian Institute of Foreign Trade that's located in Delhi and Kolkata are known for their master degree course as well as research course. Now I will come to the job opportunities that are open for an economist. So I categorized into three different headings so one can pursue job in government sector then job in academic institutions and corporate sectors. Let me start with job in the government sectors so one of the prestigious job that is associated with economics is Indian economic service so if somebody wants to join Indian economic service then he or she needs to sit for this particular exam conducted by Union Public Service Commission New Delhi and if someone is selected in this exam then you will be working in this institution this is a government of India not block, not block so basically those who are recruited under this prestigious service they work with different ministries such as Ministry of Finance, Ministry of Commerce and Trade and Ministry of Industries and then starting salary ranges from 70,000 above and above and eligibility is post graduate in economics applied economics or business economics. Next job, prestigious job associated with economics is one can work with RBI Reserve Bank of India, the premier bank in the country the central bank of the country and every year Reserve Bank of India they recruit people and to Reserve Bank of India every year they conduct this exam and to work to appear for this exam one needs to have master degree in economics also people with MPL and PhD are preferred and if one can crack fix he will be working in Reserve Bank of India and the annual salary starts from 12,000 to 14,000 then other jobs that are associated with economics one can be employed as an employment officer and in the union government and the requirement is a graduation in graduation and post graduation in economics apart from that one can also work in NABAR the prestigious bank that works for the development of agriculture and rural development in India so NABAR recruits at two different levels A grade assistant manager and B grade manager for A grade the eligibility is graduation in economics with 50% marks and age is limit is 21 to 30 years and the starting salary is around 60,000 rupees and then for B grade manager the eligibility is post graduation in economics and the starting salary is around 73,000 rupees apart from the mentioned job opportunities all the banks in the country all the commercial banks be it public sector bank or private sector bank they have one post exclusively reserve for economist and the post itself is called economist so you know in India we have many banks and almost we have 22 more than 20 nationalized banks that is all public sector banks and also we have many private banks and over there the number of branches and the operational banks are increasing so there is enough scope for an economics economic student to be absorbed in these institutions then again one more job that is associated with the center government that is statistical investigator and for this particular job as well economic graduates are preferred so if somebody is selected under staff selection commission that is a commission to recruit people they will be working with MOSP and two different specifically two different organization that is called NISO national samples organization and central statistical organization and then as I told you the attribution eligibility is post-graduate degree in economics from university or both and again the salary you can see in the screen it is around 70 to 80,000 per month these are the different job opportunities under central government and then also the type of job and the past it is being displayed now let us come to the job opportunities in Nagaland so one can work as an economic and statistical officer under economics and statistics department government of Nagaland then statistical inspector under economic and statistics department then we have district evaluation officer and planning assistants so these four jobs are exclusively reserved for economic students and the eligibility being MA or BA in economics now if somebody wants to wants to join as a teacher or want to have a career in academics then one can join as a subject teacher also called PGT teacher or post-graduate teacher in the high secondary schools and eligibility is MA with 50% so if you want to be an economic teacher then you have to have MA economics with 50% mark and be at degree now if somebody wants to work in a college then one needs to have an MA degree with 55% marks and he or she needs to pass NET or SLAT exam NET stands for national eligibility test and SLAT state level eligibility test and if somebody dreams of working in a university then he needs to have MA NET SLAT and PhD just to give you a picture of higher education instead institute in the country in India we have about 967 by now I think it is around 1000 higher education institute in the country and most of the universities have economics as a subject so you can understand if you want to work in higher education institutes you have ample opportunities and day by day number of institutes are increasing and in India we have 39,000 colleges and I can assure you that more than half of the institute number of more than half of the college they will have economics as a subject so you can understand the importance of this subject and the job opportunities associated with this particular subject then you can also work as a researcher and you can start as a research assistant project coordinator research associate senior fellow and research fellow and in the bracket I mentioned the eligibility criteria as well and I can tell you that in India we have maximum number of research institutes in social sciences and they are associated with economics some of the premier research institutes in the country are New Delhi this is a research organization okay they provide consultancy services they undertake research projects research project for for clients all over the world then we have a national council of applied economic research then RIS New Delhi Asian Development Research Institute Institute of Development Studies Kolkata Center for Development Studies Trivendrum and these are other prestigious institutes so all these are prestigious research institutes in the country where a student of economics can be recruited and then apart from this government job or in the corporate sector also we have many different many posts for economics economics students so a degree in economics or MA in economics may help you to find may help you to be may help you to get a job as a financial analyst in an organization business analyst, data analyst is senior financial analyst research analyst so these are the jobs associated with economics in the in the corporate sector then if somebody dreams have higher ambition you can also work in this some of the premier financial organization in the world World Bank International Monetary Fund and United Nation so lastly India is known to produce famous economist these are these are some of the famous economist and I want to I want to inform you that two of our economists they were awarded Nobel Prize as well in the year 1999 and recently so Banerjee they have their roots in India and they are they are working their work was related to India so with this I would like to conclude thank you we will have a question and answer session okay thank you very much Sir Teba for your very helpful and insightful presentation so I hope everyone here has benefited a lot and then enhance your knowledge regarding the scope of economics as well so anyway moving on to the next okay we have a short speech from Mr. Shako Iconyak he will share his experiences at the college and then of course regarding this economics subject so I keep the time to you good afternoon everyone first of all I would like to thank the faculty members for giving me the privilege to experience with everyone and secondly I would like to concretely each and every HSSLC pass out students for preparing the exam today I'm here to share my experience in few words well would you believe me if I say that I didn't knew which subject to offer during the last day of admission at college but after I opted for eco in my first year all I was told by everyone was that I had enrolled myself in the toughest course of the university the course indeed was a bit nervous but not that difficult it becomes difficult when we try to caught everything in the last minute my first year experience was the best one and one good score more marks as they are only simple match and statistics provided in second year it was a bit bad for me as it required more diligence lots of practice which I like however third and fourth year they are more easy and understandable thinking about all such experiences and learning I always think about a teacher who have always advised me with a quote the more you try the more you learn and believe me I have learned a lot and I've been shown various scopes or ways to follow these to come so to say my life has been pulled into the right path from a blindfolded illusion living aside when we talk about economics all that comes in our mind is mathematics and diagrams but let me tell you economics do deals with other things too such as day to day currency activities international trade business banking etc lastly but not the least economics have always interest me when it comes to international trade business banking as it help us to update ourselves with current situation all over the world and it has always raised my willingness to learn more but honestly speaking all such things could not have been possible without the effort of teacher who are always ready to help the students in every situation just like their own chat and trust me with the facility provided by the Dezo College which takes place in whole other level which helps us to advance ourselves not only in booking knowledge but also in every activity that we do and the best thing about economics is that it gives you a lot of choice the only thing one need to do is choose one and follow the right step to achieve with this I would like to wind up my sharing and all of this for your future make the right choice good luck and thank you thank you very much Mr. Syapai Konyak so as we come to the end of our program now we will have the time for this Q&A session so I keep the time for the audience for your questions if you guys have any doubts clear if anyone has anything to ask regarding you can either use the message box or you can enter okay I think you are not audible okay please hold on a minute alright please take the next turn alright so he is in law so he wants to know why economics subject is not so popular than the other subject in Naglain okay very interesting question so I think this question has been lingering for a while isn't it because this question has been there since when we were students also you know it has been for quite some time but I think we don't really have the clear cut answer to this but one reason is quite clear that is I think it is because of the fact that this incorporates this mathematics right because just see when students they choose this art stream after geometry calculations right it is because they don't find this science in maths subject interesting right so most of the people what they do is that they have this fear of mathematics or they don't really have this interest in mathematics so economics it involves you know a lot of mathematics that is why maybe that is the reason why people they try to avoid you know applying for this economics subject that is what I think but in real sense to be honest I think economics this mathematics involves you know economics it is not really right because it doesn't really involve this advanced levels of mathematics it just involves this elementary source of mathematics like you know algebra and then calculus and statistics right which are quite very if you just you know understand the concepts and then you know it is very helpful in understanding in detail the theories of economics right so there is also a saying that you know mankind has shared what they don't understand so I think that is one of the reasons to see your questions okay since you know if you're ready with the question then you can try again that's fine so in the meantime if there's anyone that would also like to ask or clear your thoughts please to share your questions Yamiyonga you will take that question or I will take that take this question okay fine sir you take that question okay economics have two main branches micro and micro economics so which one is preferred see it's when you study economics it cannot be knowledgeable and you have you will have entire knowledge of economics by studying only one particular paper so you have to understand that all the papers are related and if you see and there are various paper but then the foundation of economics is micro economics so if you want to do or if you want to make a career and almost all the theories economic theories are built on micro economics so I don't think you can prefer micro or micro or any other branches of economics rather all branches are related yes of course some paper some branches are specialized branch so if you want to if you want to go for a particular like when we go for research or PhD we will focus on one particular topic so if you are thinking of say for example research for PhD then you can of course think of a particular branch otherwise you need to study all the branches fine I think I could answer your question any other question if you have please do type if your voice is not yeah network is not good what will be the benefit of agriculture economics? Yamyanga you want to take it's okay sir you can take agriculture economics it is a part of economics only it is a specialized branch and it studies the different crops and then it is it basically focus on agricultural sector how see we all know that at some point of time our country was a food deficient like our country could not produce enough food grains so this particular branch of economics focuses on certain food grain production and yeah certain food grain production and it's related to how the agriculture productivity can be increased and it also studies about other agriculture related activities such as dairy farming floric cultures and all and also you have to understand in India more than 50% of the people are living in rural areas and their livelihood is dependent on agriculture so in our country if we have to uplift okay so it is very important that we focus on this particular sector and agriculture is one of the branches which focuses on that particular sector okay so this is what I have to say related to agriculture economics anybody else any other questions what are the some special branches of economics so economic is a very dynamic subject okay and it is related with all the other social science subject as well so you can have political economy and then you can have energy economics you can have research economics okay industrial economics so these are these are some of the branches of economics okay special yeah these are all actually when this particular energy economy it is related to the energy sector okay agriculture as I told you related to the agriculture then industrial you have industrial economics you have development economics development development economics is related to the economic development of underdeveloped countries and this there are so many theories that has been developed okay model has been designed how we can develop the underdeveloped countries okay if you have other questions please see commerce study and economics commerce economics and girls entire commerce within it so economics it is the study and practice of how people allocate resources okay and commerce is a specialized branch you can say okay that within the universe of economics and it is a specialist branch you can say and it has different dimensions it looks into the business aspect so if I have to say the business is the art of selling and selling goods and goods and practice of practice how goods and commodities are sold so economics is the universe and commerce is part of it so commerce operate within the periphery of economics this is what I can say so you have any other question this industrial economics deals with industrial economics deals with industries so if I have to give you an example see in India in the 19 after independence we did not had enough enough industries manufacturing units in the country so so the government of India designed designed economic policies the government of India started planning in the country in the planning and then we also have five-year plans and industrial policies so industrial industrial economics deals with it is a study and if we relate to India so it is all about all about studying the industrial phenomena designing economic policies that will help help the growth of industries in the country and this particular branch is related to that and it also evaluates the needs of different industries different type of industries different sectors so this particular study the branch of study branch of economics deals with industry we will cover this so in India the government of India from time to time came up with new industrial policies and the latest being in the year 1990 and thereafter of course we adopted globalization globalization all this is related to the all these policies related to industries all these policies are related to industries and it is a subject matter of industrial economics ok this is an interesting question which branch of economics to opt in masters if wants to pursue career in teaching and in painting now see if you pursue your masters then you have to study different branches of economics you have to study micro you have to study mathematics you have to understand statistics public finance ok so everything so you cannot study one single paper if you want to do your master so masters if you do your masters then you will have 16 paper and then it will cover at least 7-8 branches of 7-8 different branches of economics ok this course is designed so that you have understanding of different economic concepts and then you can relate ok when in later years when you want to develop a career or want to you work in as a government organizations you can relate the concepts that you learn from different branches in painting you can design some policies ok so you cannot do your masters single paper but then rather you have to study multiple papers and if you want to have a career in banking see banking is not only about economics it's more than that so if you want to work in a van you got to have your maths right you have to have your communication good communication skills you have to have good reasoning ability so when you sit for any banking examinations you have to know English good communication English then you should have aptitude for mathematics at least you should be in a position to solve simple mathematics profit and loss something like that calculating interest compound interest all these things and have the good reasoning ability so if you are working in a clock so these are the requirements but if you want to of course the knowledge that you learn from economics in the paper banking and finance it will also help you to understand how a bank works and how a bank functions but if you want to have a career as a bank manager so it is mandatory that you have to clear a paper on banking and then you have to have knowledge about decent economic phenomena you have to understand the functioning of say RBI other financial institution so this part if you have a degree in economics this part you will learn what you do, what you pursue your PG or a graduation in economics but other things such as mathematics and say for example reasoning ability and then knowledge about management these things you have to learn by yourself so just an economics degree may not help you to get a job as a bank manager of course the knowledge that you will be gaining by pursuing a course in economics it will help you 25% of your but other 75% you have to you have to learn by yourself okay now the best university so you have only one good university in Nagaland so it is basically Nagaland University but then in North East if you say what are the good institution in that case I can tell you that we have IIT Bahati and then we have master degree course as well and not exactly in economics but master in development studies you can pursue that course as well and IIT Bahati they do have PhD in economics so somebody wants to wants to study in the North East I think this is one of the premier institute also North East and Hill University is one of good institute and then Nizaron University is also other than Bahati University so these are some of the some of the good institute to pursue higher education or economics in North East I hope I am clear okay so I hope everyone is hello yes you are audible okay so I hope everyone is clear with your answers questions and doubts if there is anyone else that would like to ask any questions SBR, PO, Navard I think it is all depend on your choice okay nowadays banking has become job of a banker is not that easy I am sure you must have seen people maybe you have family members working in bank as a PO so it is not that easy banking over its status something 8 in the evening 9 something like that so if you are talking about the life okay then I think central government job under SSC that is much better because mostly this central job it is for 9 to 5 job and I think that is much better than maybe SBI, officer PO and Navard also it is not that easy the jobs are good but then working our work and then now there is some stress associated so that is the problem it depends on your choice what do you want otherwise central government job is much better thank you any other question any more further questions from the audiences okay so it seems that there are no further questions from the audience right okay so if there is no further questions then we will just wind up here and so I thank you all for attending this short webinar for these curious opportunities in economics and hopefully all of us is benefited from this session alright and once again I congratulate for two stocks students who have just passed out to class 12 and I wish you all the best in your future endeavors so thank you so anything that you would like to add no I just want to thank everyone for attending the webinar I think this webinar will help them to make their choice to choose economics that's all okay alright thank you all I wish you all a good day and have a great time