1990 under the term mapping the brain and its functions integrating enabling technologies in a neuroscience research with Joe Martin as the chair and co-editor of the report Constance Pachura and You can see here that there was a long list of representatives of the public and the academic and private Domains and Sure enough here's vent surf Representing the new age of the internet. I Had the privilege of co-chairing a subcommittee of the of the committee with him on the diversity of neurons which were impressive and and to him and I Made it clear to him and everyone on the committee that Neuroscience data are much more complex than sequence data The genome project informatics is trivial by comparison One of the important things that the committee dedicated itself to right from the start was that all Information needed to be part of this What was conceived of is this? Integrated map of the brain and this represents what Sean has already shown you the levels from genes and proteins up through cells and circuits to behavior And I think that was a key for why we are all gathered together here to pursue all that range of disciplines and data that Sean told us about Illustrated The some of the key Recommendations of the committee where that there should be a long-term goal of Multidisciplinary multi-level mapping of the brain that there should be the development of integrated and Interrelated databases. I'm just Extracting here from the recommendations specific recommendations and finally that in rather than having one big giant monolithic program that a Static strategy should be followed of pilot projects dealing with the diverse data by actual R01 type program projects projects individual projects The I think it's appropriate to recognize The initial leaders of that human brain project That started us off Steve Koslow the founding director along with the co-director Michael Herta We opted for the title human brain project To emphasize the vision that we had that would be comparable to the vision of the human genome project But it became clear That I the real Challenge we had was to develop the tools in order to reach that goal of an integrated human brain project and So the term in neuro informatics Began to emerge and I thought it was interesting to try to find out when the term actually Evolved the earliest I've been able to find Was the establishment of the Institute of neuro informatics quite separate from the human brain project of course at the at the University and the ETH of Zurich With Rodney Douglas and Kevin Martin in 1995 There was then a volume By Koslow and Hurt on entitled neuro informatics in 1997 We did a review article for trends In 1998 that used the term And then there were following volumes that used the term as the as the overall description of These various tools and databases that were beginning to emerge We can discuss later Others who may have Sight know about citations that are earlier than this So an important part of the recommendations of the original committee was that diverse data should be gathered and integrated in terms of computational Quantitative computational models And that then meant that The rise of neuro informatics would be closely associated with computational neuroscience computational neuroscience had its origins of course in the Hodgkin and Huxley action potential model in 1952 That was the 60th anniversary of that publication those Five publications was held in Cambridge, England just earlier in the year At that time We also Were part of that celebration because Wilfred Rohl then introduced Compartmental modeling in the 60s as represented here the compartmentalization of branching dendritic trees plus the representation of synaptic potentials and so from those two Publications we date the origins of computational neuroscience. I joined Rohl in the 60s and together we applied a Hodgkin-Huxley like model of the action potential together with the compartmental analysis approach of will To olfactory bulb neurons and mark has mentioned that this led then to a compartmental model based on electrophysiological recordings that predicted a dendrodendritic Synaptic interaction between mitral and granule cells in the olfactory bulb that predicted these actual Side-by-side Excitatory and inhibitory synapses mediating lateral inhibition of mitral cells to the granule cells So as Mark said this could well be the first Example of a micro circuit It includes of course everything from the synaptic level to the dendritic level and To the micro circuit level so it represents the sort of goal that that was envisaged envisaged in the original human brain project meetings of integrating data into computational models and In the succeeding years we built that model into the sequence of Stages of Processing that take place in the olfactory system from the initial transduction of the order information contained in order molecules in the olfactory epithelium by the olfactory receptors to the representation of that information in activity maps in the glomeruli the processing of those maps by the mitral granule cell lateral interactions the construction of a content addressable memory in olfactory cortex and on to orbital frontal cortex Within the prefrontal cortex the highest level of the brain Where perception is carried out? so to support that work we developed a number of digital tools and In our review in 98 we Summarized some of the tools that were needed in general and that we then proposed to develop in specifically and that led to the construction of what we call sense lab a long-term effort to build integrated multidisciplinary models of neurons and neural systems that includes several databases related to the Specifically olfactory problem, although it has a general interest because the olfactory problem starts with the largest gene family in the genome the olfactory receptors of which there over a thousand in virtually all mammals and so we In the early efforts to sequence the Genes by several laboratories in the 1990s They came to us and asked if we would construct a database that would support this community effort and starting with that we have added to the Sequences that have been generated over the years and there are now over 14,000 Receptor sequences in in the ORDB and if there's time I at the end I could come back and I show you How that database works? But I also have a demo where I can also show you that for those who are interested We also have a database of the odor molecules interact with the receptors and An odor map database of the maps that are generated representing the information in the order molecules But I thought there would be more interest general interest in this group in our neuronal databases that start out with a database that represents an inventory of the receptors and channels and neurotransmitters that are found in given cell types With then a connection to neuron DB which represents The expression of those properties in different parts of the neuron then how those are incorporated into models of both for Channels and neurons and finally into microcircuits So it's here that I go on the high wire and Let's go to a browser and I thought that the essence of databases and digital tools is how they're actually used at the desk or In the lab when you've got a few minutes or a few seconds to look up something And so it seems to me the key to the tools that we're developing is How accessible and how quickly usable they are so I'm going to try to show you that now I May only demonstrate that it's not feasible in a lecture hall, but let's give it a try so our first database is cell prop DB and This is a resource That is intended to serve as a repository for data on gene products expressed in different brain regions Support research on cellular properties gateway for inputting data into canonical neuron forms and neuron DB Identify receptors across neuron types to aid in drug development Serve as a first step toward functional genomics and the teaching aid so we can go into the The database and we have a number of cell types represented our interest Of course is primarily in the olfactory bulb But almost as much in comparing the properties in the system We're working on with properties in other neurons in order to carry out a comparative analysis that gives a context for understanding any given system and I think that comparative context is one of the main themes. I'd like to get across today and also With the philosophy of sense lab. So here we have the olfactory bulb mitral cell and There's a representation of it morphologically and here's an inventory of properties That highlighted are the profile for the mitral cell And so you can see the receptors currents and transmitters Are represented here and so let's say that we are interested and so this gives the profile for the mitral cell now, let's say that we're interested in Comparing the mitral cell with GABA Receptors with all other cells that have GABA receptors So we can go down here and click on that and this immediately brings up then a subset of cells that all have GABA receptors on Them and so you can see that this includes both principal neurons output neurons and various kinds of inner neurons as well across many parts of the nervous system Some of which one may be aware of like the Hill campus others not such as the retinal ganglion cells or cells in the dorsal cochlear nucleus We can in addition to a single Property put in a variety of any any combination of properties that we think might Represent some significant kinds of activity and so under currents we can we can ask for transient sodium currents and a currents for example and Go to submit those and this immediately then gives us a somewhat smaller subset of cells now that are Expressing that combination of properties and so this I You can see that this could Be used for any particular set of properties that you're interested in but I think the main point here is that we're beginning to move toward a multi disciplinary multi-field Approach to Identifying families across all of a particular a set of Entities in a database so like in a gene in a sequence database you can look for particular combinations of sequences and Identify new classes and families of receptors or channels in the same way we can do that for different types of cells in in the in the nervous system however It's obvious to most of us who work on cells that it's not just The expression of different properties by a whole cell But it's where in the cell those properties are expressed because a cell contains a number of compartments virtual compartments In which integrative different types of integrative action occur and so for example for the mitral cells we have proximal region a middle region and a distal region of the Primary dendrite. This is the part of distal part out in the glomerulus. The same can be said of the lateral dendrites the soma action axon hillock axon and Terminals complete the sort of basic compartmental structure of a neuron. We call this a canonical representation of the neuron it enables us to identify the major integrative sites in a cell But it also means that if we do this for all cells we can search across Different compartments of different cells and be much more specific about this new classification way of classifying cells So we then go to our next database. We're right there in neuron DB And so here's that same cell and now here's the canonical representation of it in a compartmental way And now we can bring up the data and now instead of being for the entire cell This is just for the distal apical dendrite and now we can ask And so first of all we see that this is the integrative structure for this compartment and it's more than just a Gabba receptor or glutamate receptor. It's also the intrinsic currents and in this case It's also the fact that this compartment can release glutamate It's presynaptic as well, but let's now ask our same question How about all distal apical dendritic distal compartments of dendrites that express Gabba Gabba receptors and here we have now a subset. So you see it's a smaller subset than we saw with the whole cell Representation now at a compartment at a distal Dendritic compartment level. It's a smaller subset and again it crosses both principal neurons and interneurons So now we can ask the same question that we did before of adding in other kinds of intrinsic currents So let's ask now about our transient sodium current and our a current and now you see these have a completely different significance Because the transient sodium channel is of course present in many most neurons that are generating actual potentials in their axon But now we've got a distal apical a distal apical dendritic compartment That we're also asking does it have the ability to generate action potentials and are there also a currents? Which usually are present in order to balance out that excitability and so now if we search We see that there that there are that there are in addition to the mitral cell There are the ca1 pyramidal neuron the dentrate granule cell cerebellar-pikinji cell and the neocortical pyramidal neuron also have that this particular combination of properties and now it gets it's getting interesting because that means that Active properties can be involved in the integrative action the activity that's taking place in that distal compartment Now at this point you might be you might be interested in The fact that the ca1 pyramidal neuron is also part of this subset So let's just go and see what it looks like and immediately. We're in the ca1 hippocampal pyramidal neuron and you can see it has its own set of Properties and we could fill in all of these and look or many of them and look for different combinations across this This are other types of neurons. So that indicates the kind of Exploration one can make of the integrative structure of every nerve cell in the database and In a within a comparative Context of relating it to any of the other neurons in the database and bringing out new classes of neurons that have particular combinations of properties in addition We build connectivity into this so that we specify the connections that are responsible for the inputs to the receptors and For the connections made from the output from the axons or from the dendrites and in the in this in this particular case And so we are building in then what can become the basis for the connect to them a micro connectome of these cells and Also within a comparative context of other what one can call micro connectomes and then finally we provide annotations of classical references for the first demonstrations of these properties in order to establish the They're defining characteristics Okay, at this point we might say well We're interested now. We see that there is evidence for these different kinds of receptors and currents We see some of the classical references to it What kind of models have been built based on these? experimental properties and we can go immediately then to model db and Here for the mitral cell Is a list of the different kinds of compartmental models of a mitral cell and I just show for as an example a Model that we did a number of years ago with Michael Heinz in the of the mitral cell and This indicates how one can go to the actual files for running that model This is for the transient sodium and The key the first key is that you can run the model immediately. You don't have to build this model From the publication as one used to have to do one can actually take the model as it was Run for a paper and immediately run it yourself So it comes I think as close as we can get to the way that every publication needs to provide the specific information about the agents for Obtaining those results so that they can be repeated and that's a key for computational Neuroscience is that we've got to be able to repeat those experiments by other labs In order to build on the finding and the key here in the next key is that each of these properties can be swiped and changed so that this model can become your model if you as you Begin to run it and have other info have other kinds of data that would provide you with a way of running it in a new way so we can also then go to model DB the home page and explore the Inventory of the models in many different ways so by model name We can see that under model name. We have 734 models now each of them curated by Tom Morse in the lab you can also explore them by first author each author or by Region here is by cell type and so you can go in and find a Model in your particular region that you would be interested in Here are by transmitters and these are the different kinds of cells that are GABA ergic or or Miturgy or whatever we also have Different simulators so although We have our own interest in the simulator neuron because Michael Heinz is one of the group and has maintained neuron for well over 20 25 years We have a number of other simulators that are represented you can see here There are over 70 different simulators Matt lab is well represented Genesis is well represented and so and so forth so That that illustrate indicates that whatever a simulator you you use Will will probably be represented in one or another of these these models We can also search by Author so one of the classic models is oopies of the olfactory Mitral cell as well as others here So therefore by him and you can go in and examine those as well So this illustrates then the The aim of getting of using models to integrate the information in the as represented in cell prop and in neuron DB into these quantitative models for For each each cell type and then finally we go to micro circuit database and here we have Started to build up the models specifically representing micro circuits and here we have Something like 180 or so of these kinds of these kinds of models that are represent both realistic micro circuits the kind that are built on realistic representations of the neurons as I've shown you in neuron DB and also connection as networks that are of the artificial neural network type Okay, so I think we're in reasonably good time here So let me now Let me now go Hold on. I think we want to get out of this and go back to there So now we are back in our PowerPoint So now I'd like to show you several ways that several of the kinds of results that have been produced by this Using the information that's in sense lab one is a paper that McKelley, Miliori, and I did number of years ago in which he Made a preliminary effort to relate the expression of different. I am ionic channels I Relate them to the different morphologies of different kinds different kinds of dendritic morphologies and so starting out with synaptic inputs activating Cells with large or small temporal windows he was able to work his way through a Decision tree that enabled him to identify the sequence of decision points that produced in the expression of properties that produced the properties of the different kinds of cells Including mitral cells neocortical and ca1 cells and Phthalomocortical and Pekingia et cetera on this side. So again, that's a new way of classifying cells in relation to integrative properties That is that cuts across the different kinds of morphological types that we tend to be very very much fixated on And at the microcircuit level we with McKelley and with Tom McTavish and Michael Hines have been Developing a scaled-up model realistic model of the mitral cell granule cell interactions And this represents current stage we're at in which we have 500 mitral cells receiving input From glomerular activity patterns is determined by Kinsaku Mori's experiments using intrinsic imaging Interacting with 10,000 granule cells and this is a site as shown by Mori's Maps where there is a relatively weak input to a set of mitral cells and this shows over time the emergence of that excitatory activity with the emergence of inhibition Ladle inhibition on either side due to the activation of granule cells starting at this at this point in the learning process this is a much stronger input giving you much stronger lateral inhibition and So forth and the key here is to show how extensive Ladle inhibition is within this region of the of the olfactory bulb much much more extensive than I've been previously thought but as is going to be needed in order to explain these distance independent nature of the processing that takes place within the olfactory bulb There's a lot of interest now in systems biology and in systems in terms of Different systems in the in the nerve system What we have in the olfactory bulb is a need to recognize that those systems are Controlled by the respiration of the animal in delivering the sensory stimulus to the sensory receptors and here we're this is a Recent experiments published by Matt Phillips In which the lateral inhibition of the mitral cells differs Depending on the phase of respiration whether it's inspiration or expiration and you can see that lateral inhibition is sensitive to the phase of the of the respiration and so that means that our systems biology Has to take account not only of the neural systems, but also of the body systems that are providing the input and so That I remind you that all of this is aimed then at this sequence of operations that's taking place within the microcircuits of this of this system from the olfactory bulb olfactory cortex orbital frontal cortex and so here I think I'm going to go back to the to the high wire because I'd like to now and By indicating the context for sense lab in relation to Some of the other major efforts that are taking place in order to develop neuroinformatics tools and to move toward this integration and the main theme here is that INCF and neuroinformatics has Now focuses very largely on tools or predominantly on tools because it's been such a struggle From the start with the human brain project to develop the tools in order to work toward this goal of Brain integration and in fact it was a problem with the human brain project During the early years of funding because people said well, where's where's the result? and in fact it was a much of the effort was put in by the Brain imagers for example just warping the brain and being able to compare the results in different labs and I remember when Mike gazaniga as editor of the Journal of Cognitive Neuroscience I Suggested a policy in which all papers submitted to the Journal of Cognitive Neuroscience should provide the data sets for the generation of those Results there was a tremendous outlaw from the Field because they were reluctant to do that and it was only after a couple of years when a review committee gave Strong support for this idea that there was a general recognition that this is the way you share data in that particular field You share your data sets so that people can see how the data was generated and can do their own comparisons And so I think there have been so many issues about building databases and Building the tools that we've lost Site a little bit lost site of what the real goal is and that is the integration and So I'd like to give an indication of how we might move toward that in that integration In terms of the tools will need to do it and the integrative approaches so Let me Start out here So one of the things we need to represent we need to have a general Recognition of What the resources are that go beyond the particular ones that we're building and One of the ones that I think is important to know about is the IU FAR no manclisher. How many people know about IU FAR? Okay, few people so here's here's for the rest of us I I would probably be among the ones who wouldn't be so aware except that I was put on the committee to to represent all factory receptors it turned out that the number of all factory receptors is greater than the number of all the other gprs CRs put together and They have developed a nomenclature for all the others, but it We found that it was just not possible to apply it to the olfactory receptors so it's the illustration of Some of the problems in developing general Nomenclature that apply to all parts of the system. So here for example our G protein couple receptors and Here for example are the five hydro hydroxy trypone receptors and if you go into any one of these You see you bring up a Tremendous amount of data here Tremendous amount of data about agonist antagonists Transduction mechanisms tissue distribution so forth. So this is definitely a resource that we ought to know about the same The same is available with regard to ion channels. So here are sodium channels for example here are One kind of sodium channel and again you go down here and you can see the very rich amount of Information there is annotation and all the rest about any given channel type so again, I think if we if this level is going to be a A Essential part of building up the the multi-scale Integrated view of the brain that we're all after then we need to have be aware of the Resources that are going to be adequate to that so the next I'd like to show is the NIF So Now if you key the NIF in You'll get the national ignition facility and there's no way we can get rid of it We're working hard. We're her working hard to displace it but And now that we're in now that we're in Germany. We can't even get up to As high as we really ought to be but nope that's that was the wrong one So how about this one here? Here we go So here we are with the NIF and I assume Most most of you have heard about the neuroscience information framework led by Marianne March on She's here yet but the This is a portal with a tremendous amount of Functionality built into it and you'll hear more about it in later in later Talks, but I thought I what I would show you is something that we're involved in and that is if you go down here to Neurolex and And go to neurons in the hierarchies then you get a list of neurons of Subcategories of neurons is the neuron types That is now up to over 200 around 250 So this is a much more comprehensive. This is a truly comprehensive attempt to Characterize the main types of neurons throughout the nervous system. It will include both vertebrate and invertebrate and so I the One of the examples I wanted to show of how this works is in the amygdala here So here is How each of these entries we're aiming to provide for basic information and then a minimum of Specific properties soma dendrite axon specific properties and intrinsic properties And so you see this is similar to cell prop But it attempts to identify properties that become the defining properties of a given cell type And at the same time to enable us to go in and for example with GABA to identify All of the Cells that use GABA This is one way of representing it, but there's an even better way and that's to Go back and so you you could ask what are what are all of the cells that share a given Neurotransmitter As the transmitter released and here quite quite quickly you can go and get an entire Inventory of all those 250 cells For which ones are cholinergic? Which ones are GABA ergic? Which ones are glutamatergic? Etc. And so we want to do that now For all the other properties that are listed there. So give me all the spiny neurons give me all the paramedal neurons Etc. And Working with Steven Larson. We have a small grant from the from the from INCF to engage domain experts in helping us to Identify these main cell types and their properties in different areas. I just show you the curator page here And you can see that we already have some 20 people Who've signed on to provide this information and we encourage anyone who would like to volunteer For their own favorite neuron to to let us know So the next I'd like to show is The Ellen Brain Atlas and I don't think I need to Belabor this because they'll be I'm sure a much discussion about the Resources available in the Ellen Brain Atlas But one of the things we want to do with neuron with neural X neuron and with cell prop is to link to the the different patterns laminar and otherwise of staining and localization of properties So that one can go from those properties to the individual cell types in a particular region or layer or vice versa Another another project that ought to needs to be part of this Overview is the blue brain project that Sean Hill is involved with Henry Markham in running in Los An and I think this is also well known as an attempt to provide a comprehensive description of the court the Cerebral cortex in terms of these different layers levels of organization that Sean was illustrating the blue brain project is now a Core site for the proposal for a Blue brain for a human brain project. So now after the blue after the human brain project ended in 2000 around 2005 in the US INCF came in and now the the blue brain project Came in and now the human brain project and so that has its own website as well And I thought I should just indicate I think some of you may have heard that this is a large very large program that they're competing for This is not a program in biology or in neuroscience the human brain project you Sean can explain further is Applying with it for funds within a very high technology cutting-edge technology Grant program. It's the I think the only one represented in neuroscience because they proposed to use cutting-edge computational and other other Methodologies, but the the research areas here are very impressive in bringing together these different Areas of research that I can't I can't get down Here we go So you can see that there a whole range of issues is going to is going to be included in this trans European Project This again represents This original goal of the human brain project of doing the actual integration and it shows how Comprehensive this kind of integration is going to need to be not only for the the scientific aspects of Brain organization, but all these other aspects of it the medic medical the supercomputing aspects the educational aspects and the ethical legal and social sciences aspects Finally We don't want to forget the connectome project and How many here are part of the connectome project? Not so many But this is a tremendous project in the you mainly focused in the US For carrying out a comprehensive analysis of the human Connectome and so I I don't know whether we need this big a program tens of billions of dollars to do the the to do the Macroconnectome, but we certainly I think want to think in terms of a micro connectome project That would connect with the macro connectome project because after all why do we have a macro connectome? It's to connect the parts of the brain. They're actually doing the computation So let me end by Going back to So let me let me go ahead here. I think we were here Okay The future So what I what I would propose is that we need to work toward our Principles of comparative neural systems, so we each work on our own neural system, but I think comparing systems Across other parts of the brain comparing systems across other Species I that have and the system we're working on and comparing across Birdabrit and invertebrate as well. Here's an example of what I would call the comparative approach I did this study several years ago In the olfactory sister in the olfactory cortex. We've identified a basic circuit in which the input comes into the apical dendrites and the apical dendrites then the Parameter learns the parameter learns and have recurrent excitatory collaterals recurrent inhibitory Circuits feeding back on them with some feed-forward as well We propose that this is a basic circuit and indeed you can apply this in with minor modifications to the hippocampus and to Turtle dorsal cortex as as Kriegstein and Connors did One can then propose that Neocortex arose out of a kind of a duplication of that organization so that one has superficial and deep Divisions of the Neocortex layers 2 3 and 5 5 6 particularly in which and their this basic circuit is embedded in each one This has been used for example Recently by Fritschoff-Helmschen At a genelia meeting and we attended in which he showed an adaptation of that to show How it might help to account for the results that he had got in identifying different In kinds of inputs coming in here from the VPM here from the posterior medial Here from other areas of cortex So that this provided a way of thinking in an integrative context about the about his own analysis of these pathways in the cortex here is an example of the Kevin Martin Rodney Douglas Neocortical Canonical microcircuit of which has two three and five six with recurrent Excitation with current inhibition in very similar ways essentially the same circuit that I showed you and so I think you can see that there are indications of a convergence of the integrative approach And I think we should continually look for these convergences as ways of beginning to build a Consensus representation of the map and so a brain map and so I leave you with the question a human micro Connectome project is that in the future for us? in which the micro macro connectome connects the the micro connectome and that maybe this is a A Goal that the NIF can Provide a driving force for as well as the INCF And finally this is the sense lab team Perry Miller has been the backbone of our informatics Michael Heinz Has been the backbone of our computation and all these other Colleagues have been just a wonderful group to work with. Thank you very much coffee. Yes. Yeah, sure questions In the part of your talk where you were discussing the computational models in your your databases and keeping track of The models in a way that they could just be in sort of installed and run right and I wonder if you could say a few words on Challenges in doing that in sort of making sure that you're keeping up with the literature on that So this is a very good question. So if you make models easily available for running, I think what you're saying is if anybody can run the models maybe they don't have the background in understanding the the nuances of the data this is one of the problems of elect physiology Particularly that you really need to have a thorough understanding of the properties in order to begin to build your own representation of a Particular model is that is that what you're doing? No That's a great answer, but it's not my question. So my question is so you've got a real if you're doing that Which I think is extremely valuable You've got to kind of keep up some find a way to keep up with all the new models that are being published in the literature And isn't that challenging? Well, that's that's sort of what I was getting at Oh, okay, if you don't if you're not familiar with the field then are you running your model in In a field in which you have no you have no particular background Is that what you're saying and so you as a curator you as curating the database How do you keep the database current with the new all the new models are published or maybe I'm Overestimating the volume the database the database is accumulative So all it it starts it goes back to Classical models like made in the Sonowski in 1995 and it's there they're all there and you can Run them or you can update them as as you wish and You can also search you could also Determine when you search them which are the latest ones and which are which are the which are the classic ones Hi, thank you so much for that talk Actually, I've got pages and pages of notes trying to relate what you've been doing to the areas that I work in But I was thinking about particularly about your your databases where you have you know neurons And here's their properties and here's their receptors and they seem to all be Facts does anybody ever come to you and say no I want to argue with you about that point Or do you have a representation of? Probabilities like most of the time this is true or all the time. This is true We've never found a counter example or any sort of evidence like that so one of those one of those entries was pink and that means that that's Been shown not to be present That property and so that's one of the things we want to know However, there's a recent paper that we were looking at recently that in which they've looked at NAV 1 1.1 2 and 6 and those Subtypes are all present to different degrees of different Subtypes of hippocampal pyramidal neurons and so Rapidly a database can get very complicated And but that's exactly in my opinion why you have a database so that you can annotate those complications or provide models with those Complications and let people then figure out themselves how they want to let the classification evolve It's a tremendous challenge for a classification We don't want to get weighted down by thousands and thousands of different Subtypes of neurons or subtypes of channels on the other hand We want to represent what is of active interest to most people Doing research in a particular field. What's most useful to them? I'm really impressed by so many databases Perhaps we'll hear about this later in the conference, but are there are some people who build machines database crawlers using artificial intelligence to Implement Questions that you might have in mind It did avoid so you mean in silicon You mean I would assume it would be a software machine that would crawl through the database and and use some methods of artificial intelligence to Provide some sort of understanding Yeah, I don't know how I just curious how well that it is already advanced and what what's what's happening There are others here who can answer that question with far more Knowledge than I can maybe mark your part. This is Jeff Jeff here Or maybe that can be a discussion point for later on Marianne. Do you want to answer that? Here got a microphone We always we always Depend on Marianne to so in terms of employing it formally within for example NIF The answer is it has not yet been done There are things like Wolfram alpha and others that are trying to do this for larger Datasets, but you know again the idea of a NIF would be that there are different steps involved and now that we have all of this Information being sort of unified in a platform being able to build agent that would be able to go in and query it in an AI like fashion we do have ontologies and other things that That drive NIF so there are some concept-based searches and those sorts of things But I don't think there's been yet any sort of data-driven application that goes in and tries to make sense of this massive information There are some posters on Workflows and various types of analytics that we've done, but I think it's sort of ripe for somebody to do just that It's like now that we have all this data What do we do with it? Yeah, who's going to write the algorithms? No, I so I think there is a an implicit problem of who's going to put it all together and I think we can only do that by a community effort And that's why I think the IU FAR Nomenclature is is a good example of how communities come together each of those I and channel communities made their decisions and then I you far put it all together And so I think that's how how we're going to need how we are proceeding. That's how we'll need to proceed okay, I'm wondering if you think that there might be a Limit as to how far we can go in this endeavor due to our inability to get sufficient detail about About properties for example, maybe it's necessary exactly what's going on at each synapse in order to construct us The actual circuit that is performing some function We must be very careful not to drown in detail detail The devil is always in the details. However What's important? I think is to be able to work at a more conceptual level at each level so that you can Provide input to the next level and that's for example The idea of our canonical representation of the neuron That's the idea of Martin and Douglas with their canonical representation of circuits is that it gives you a essentially a working hypothesis For what is essential about that particular level so that you can then use it to to drive the next experiments Sir I have a slightly basic question which goes to ask And maybe this borrows from ideas of systems biology that we seem to have a lot of like structural models and structural Databases of the various neuron types and the kind of like receptors present on these neurons But what about behavioral models and you know trying to go from structure to behavior to function? Are there you know has there been a curation of these behavioral models? May that be in silico or in vivo and trying to correlate from structure to function why of course behavior and You know higher level higher systems levels. Yeah, that's a that's a excellent question a very Disturbing one in a way because as you say we have been focusing on structures that we can all agree on are there our entities but the even Characterizing the functional properties of neurons and systems is something that a step that we are not yet able to take because function is so nuanced in in the Analysis of neurons and systems that we haven't yet developed an efficient way to Represent that and the same goes with behavior because behavior can be represented by bar graphs by Videos by in so many different ways that I agree that that is a really big challenge for the future sorry I'm always struck by The huge amount of data we collect and yet one of the goals of science is abstraction We all recognize for instance that f equals ma is wrong But an incredibly useful abstraction one of the things I worry about about getting caught up in This neuroinformatics approach is forgetting that one large role is to get some abstraction that you can carry around and Simplify your understanding of a system rather than complicate it with all the details If I have to carry around all of the details to understand the system Then am I any better off than I was when I had the system in the first place? And so I think that comes back to the one of the main themes that I was Encouraging us to think about and that is now that we've developed many of the tools we need for archiving the details That we need now to do the integration and the integration has to focus on the essential details that then give rise to the concepts that Move us forward in a conceptual way. I agree. I agree absolutely All right one very last question And it's a comment So At these meetings we often get questions like When are we going to abstract? I think this kind of work is always dialectical in the sense that we need to go to the details


So first thing is I want to thank all of you for coming. I also want to thank Mark Williams and Terry for organizing this, co-chairing this. I want to thank Geisinger for handling a lot of the logistical assets and really hosting this in many ways. I would also point out that it's a good thing we decided to start this when we did. Originally we were gonna start this a little later to allow some of us from Washington to fly in this morning. The federal government's officially closed in case you didn't know this right now not because of the fiscal cliff, because of a little teeny bit of ice in the Washington, D.C. area. So we're actually closed in the D.C. area to noon, but fortunately all of us decided to come in last night so we're here and we can get going. It is interesting to look out at this group and see how it has grown. I think the origins of this meeting, this gathering was Jeff Ginsburg telling us once that an advisory meeting wouldn't it be great if we started getting together? And then we had Genomic Medicine 1 and it was a reasonably modest sized group and it's grown two, three, four, and so forth. I'm projecting by the way the field is going and the way this group seems to be expansive in its thinking, which I love. I'm pretty sure by Genomic Medicine 10 we're gonna have it in Madison Square Gardens or somewhere that'll be a massive venue. It's amazing to see the depth and breadth of people interested in this and I think you can see from the agenda. We won't disappoint. The other thing I wanted to point out from the point of view of the National Human Genome Research Institute is the subtlety but I think it's relevant and you're gonna see it play out a little bit during this meeting, some of the people you interact with. The origins of this were very much around Genomic Medicine narrowly defined coming out of things we were talking about programmatically we were gonna be doing especially under Terry Minolio's leadership. I'm not gonna give you many of the details but in this previous October one the Institute went through a fairly substantial reorganization, the first one in a very long time and we created a whole new divisional structure that really I think better defined what we're doing very broadly in genomics. And the reason I raise that as Terry is the director of one of our divisions, the division of Genomic Medicine but the issues and topics and things being discussed at this meeting really are not solely in her division. In fact many of the things we're gonna be talking about here are very relevant to some of the other divisions.  And then meanwhile I'm gonna even have a few remarks to say about some of the things going on in our intramural division that I think are relevant and I think some of the other divisions they're gonna, so I just wanna make that point because our view is expansive and I think our structure very much reflects that and with time on some of these topics you're gonna hear about an update from another meeting that somebody that Derek Scholes will be talking about later. You will see how different parts of the Institute might be adopting and running with issues and topics that get raised at venues like this. So if for my talk what I want to do was to just fill in the gaps in any way. I know what some of the other members of the Institute talk about throughout the next two days. I was sort of given table scraps if people thought they're good table scraps. There are a lot of eclectic topics are not being covered by others but people told me oh you really should make sure to say a few words about the other because we're not covering it. So these are the four things that I wanna just give you some brief updates about to set the context. They are a little bit all over the place. The last one in particular is fun because I thought it'd be good to have a fun topic at the very beginning to get everybody all energized although the other stuff's pretty exciting too. Let me just remind you when I wanna start with our education efforts and needless to say this is something that's been relevant to the Institute for a long time. Many of you might have seen this recent cover and story in genome technology that focused on education as it relates to physicians. The fact of the matter is NHGRI has been interested in genomics education more broadly defined than just physicians and even within the healthcare setting more broadly defined than just physicians. I would actually tell you that it's an important component of our overall mission and as very much in line with telling you about our reorganization there are elements of educational programs that are found in different components, different divisions, different sub parts of our divisions and so forth. We really regarded as a long-term goal to advance the understanding of healthcare providers broadly defined about advances in science and technology and evidence development and this very much will be relevant to some of the things we'll be talking about throughout this meeting and clearly we recognize that these educational efforts whoever carries them out and we probably will only carry out a small fraction of what's gonna be required. It's gonna be critically important to assure productive utility of genomic information for clinical care because of all the complexities of genomics and all the different ways that it touches. When you read our strategic plans either in 2003 or more recently in 2011 our most recent strategic plan we talk about some of these ideas obviously in very simple terms recognizing that there's a lot of complexities that need to be worked through at venues such as this. Our efforts and the resources that we've created have been several and just a subset of which but at least the major ones are shown here. Some of you might be familiar with the G2C2 resource repository that's had curriculum and other resource materials for genomic counseling education, nursing, physicians assistant coming soon will be for pharmacists and that has served as a venue that has been useful for individuals in the community. Our talking glossary has received quite a bit of utility around the world as a product of our education branch within one of our divisions. The case scenarios being created within this new G3C resource which will be in transdisciplinary in nature and we'll find usage of value to many individuals. And then most recently we have an ongoing series again from within one of our divisions sponsoring and actually involving many people across the institute in partnership with Suburban Hospital and Johns Hopkins University. We have a series of genomics and medicine lecture series held in a small auditorium in Suburban Hospital but videotaped every single week that it's held and posted on our genome.gov and also our genome TV channel of YouTube and getting extensive amounts of usage. So again, we look for opportunities for these sorts of outreach and education efforts. And so these are the kind, and then meanwhile in terms of the literature we've had various involvement over the years in terms of getting information about genomics and genomics education and genomic medicine out on the clinical journals. Greg Firo and I wrote an article a couple of years ago for an education issue of JAMA. Some of you might be familiar with our New England Journal of Medicine series that members of the institute co-edited for a number of years. And then a special issue that's pending a genomics issue in Journal of Nursing scholarship Jean Jenkins has been heavily involved in that'll be coming out quite soon. So those have been just sort of a flavor of our education efforts but we look for audiences like this to tell us what are the other priorities we might be interested in supporting or looking into in the future. Moving on then again to complete change of topic I wanted to I was asked to say a few words about the undiagnosed diseases program which originally grew up exclusively in the intramural program of NIH and we hosted it within NHGRI. For those of you who are not familiar with this program it is a program that aims to assist patients with unknown disorders reach an accurate diagnosis. These are these tragic cases where have gone from hospital system to hospital system unable to come up with a diagnosis and they come to NIH in this case so far to the intramural program rigorous workup often extensive genomic characterization and attempt to identify the disorder affecting that individual. And the goal also includes discovering new diseases that human physiology and genetics. To date over 500 patients these numbers are actually old over 500 patients have been evaluated at the NIH clinical center definitive agnosis over 39 at this point and at least 16 new human genetic disorders have been identified. The undiagnosed diseases program was a pilot project that was viewed as a experimental to see what it was like and I think it was widely regarded as being extremely successful and so successful that when it came time to evaluating it's it was important to expand this put it on longer term financial footing. The decision was made by the NIH leadership to move it out of what was basically a temporary budgetary circumstance over a pilot phase and to make it a common fund project part of the NIH common fund and that indeed is exactly what's happening and we're right in that transition a commitment over $145 million over a seven-year period initially for common funds support involved not only continuing to support the intramural UDP program but expand this to a national UDP network and in fact that was a strong urging of an advisory group that we convened an external advisory group that had been helping us with the undiagnosed diseases program and we were fortunate to be able to identify resources to make that a reality. It is envisioned the creation of a network of something like five to seven extra oh by the way needless to say all common fund projects have to have institutes help coordinate and run them and NHGRI is one of the three lead institutes and centers involved in leading the common fund and in fact we have people here from NHGRI who are heavily involved in coordinating this and programmatically developing this as it becomes reality. Along the way, the idea is to create this as a network and have more robust having a group involved in this and improving the data storage access and analysis both the phenotypic data clinical data and especially the genomic data coming out from the studies of these individuals. It also will be an arm that will involve a lot of researchers to elucidate the mechanisms of disease. Oftentimes they get down to the point of having a gene identified or a genetic defect having no idea what the basic science mechanism that lead to that disease we wanna facilitate those studies that involves training and fellowship programs for rare disease diagnostics that are in the early planning phases. And so those of you who are interested and some of you might be familiar with there is an RFA that recently applications came in on for the creation of a coordinating center that will be coordinating this network an upcoming review is pending. And then RFA does our program announcement right now involves facilitating gene function studies to investigate rare and undiagnosed diseases and the receipt date is coming up later next month. So stay tuned, there will be more and if anybody who's interested in learning more there are people here like Teri Manolio, Gene Passamani who could tell you many details about this and point you in the right direction as this rapidly evolving takes place. Onto a third again interrelated seemingly eclectic topic I also wanted to tell you about another major development going on at NIH which I think touches things in genomic medicine but it's far broader than genomic medicine and it relates to the big data computational biology bioinformatics, the recognition of one of the areas of greatest impedance mismatching between the ability to generate data and being able to analyze it. And here there is some breaking news that I can tell you that some of you will be interested in either because it'll directly affect you or because you will recognize this is sorely needed in biomedical research right now. I think all of you would agree the largest bottleneck in biomedical research in metaphor and there's many metaphors it's either the data coming out of any of these new technologies be sequencing technologies or technologies it's like drinking water from a fire hose or is it like a tsunami of data whether it's an avalanche data pick whatever you want the truth is us here those of us in biomedical research and clinical research find ourselves in the big data era once upon a time just for climatologists once upon a time just for particle physicists now we're here and it is an awkward place to be at this moment in time where we can generate data far faster than we can analyze that data. Now I stand here obviously speaking as a genomicist and clearly genomics is one of the many types of data that's creating this big data problem it's not just genomics when it comes to this NIH bottleneck there are other omic technologies that are coming forth there clearly are imaging technologies that have greatly accelerated the pace of generating data either at a cellular level or an organismal level or clearly phenotypic data something I know many of you are interested in and exposure data especially as technologies become better and then clinical data which of course is very relevant. Recognizing the importance of this area and NIH feeling overwhelmed about this Francis Collins appointed a working group of his advisory committee to the director about two years ago now and for a year they studied this and then about six or eight months ago they formally issued a report which is at this URL if you're interested in reading it the report of the data and informatics working group and the bottom line is there are major changes that are now taking place at NIH because the recommendations of this report we are tackling the big data program the big data problem I'm happy to tell you about this. First of all the leadership position that we'll be recruiting for is something called an associate director for data science I've actually been asked to be the acting director in the interim but we'll be launching a search it's a very high level leadership position or to NIH director there will also be creation of a new group at NIH internal to NIH called the scientific data council that will be responsible for many things including strategic planning in the area of big data broadly defined it will also be responsible for NIH initiative known as big data to knowledge which will be a new program that'll be jump started in the long run over a seven year period it'll be completely supported by contributions from all of the institutes recognizing this is a trans NIH problem the new initiative which will begin next fiscal year we'll have four major components I'm just gonna touch on them recognizing that there's a lot under the hood here and I'm happy to talk to any of you about it at break major programs and policy changes to facilitate broad use of biomedical big data developing methods and software biomedical big data enhancing training for biomedical big data that would include kinds of data we'll be talking about here and also a staff for biomedical big data so these are all things that you can imagine if it's starting next fiscal year we're gonna be very active in getting off the ground if the funding starts then that's not that long from now and so needless to say you can stay tuned and you will be hearing much more about it the good news here is there's a major commitment at times of fiscal constraint there's a major trans NIH commitment to try to fix the big data problem in biomedical research and we're gonna be doing this in a very aggressive timetable finally and I think I'm one minute away from getting the finger from Terry Manolio I'm gonna end you on a very happy note I'll give you some exciting things going on in 2013 why is 2013 exciting it's a celebratory year for us recall it'll be the 60th anniversary of the Watson Crick double helical structure discovery and description and the 10th anniversary in April of the completion of the human genome project recognizing this as a marvelous time especially other things being tough these days we need to celebrate we need to embrace we need to talk about this remarkable especially the 10th anniversary of completing the human genome project there are many things the Institute has planned you may want to look at this URL this website is now live and it talks about a lecture series that we're gonna be having at NIH and all day symposium in April all of which will be video cast and videotaped and video archived all of you will be able to see and there'll be some like we've lined up terrific speakers for all of us and other things that will be happening in particular though what I want to tell you about is this new partnership that we have with the Smithsonian Institute where there will be a genome exhibition that will open in June of this year this exhibition is a pretty looking design representation of it is shown here is in the very advanced stage of design in fact in my hotel room is the 95% design that I'm reviewing actively and it is gonna be fantastic it's gonna open at the Smithsonian's National Museum of Natural History Vence Bonham is here at the meeting and he is spending hours a week working on this project and he and his staff it's been a marvelous and I tell you we got a shout out in nature at the beginning of this year first issue they talked about one of the exciting things happening in science and art and that's this exhibition and in addition to this exhibition I will tell you there'll be a significant amount of education and outreach planning and programmatic activities under Vence's leadership a lot of web resource materials and so forth and it's gonna be spectacular so I want everybody in this room to commit that they will come to Washington DC sometime after mid June of this year it will be at the Smithsonian Hall 23 just 23 pairs of human chromosomes easy to remember right next to the Hope Diamond hard to forget just follow the crowd and come see our exhibition it'll be there for one year after which it will travel for about four to five years around North America one of the coolest things I've been involved in and I've been involved in some pretty cool things so this has been a lot of fun and we're happy to tell you more about it but I wanted to end on that note so I will stop there and I'm happy to take any questions, thanks. Thank you, Eric we may have time for one or two very quick questions seeing none Mira, why don't you go? I figure too You can definitely catch Eric throughout the meeting so please do so Mira you can go ahead and go up there's one other person that we should highlight that we didn't and that's Gene Passamani who introduced himself with NHGRI and he really has been key to pulling all the organizations together and organizing and we'll be working to summarize the output of the meeting so we wanted to identify him as a key contributor so thank you Gene.


All right you guys. Let's do that again. The door. The door. Blows off. Wait, completely off? Yes! Cilantro! Build a pan with whiskey? Yes. What? What? What? Hey everybody, welcome to the show. As always this is a show about failure. It's about screw ups. It's about the tenacity that it takes to start and run a business. Tonight we're going to be talking to Radiator Whiskey. It's a local place here in Seattle. Pike Place Market. And they are all about meat and whiskey. That's what I know at this point. But as always our resident bartender, mixologist, Mr. Jack Sanders. Jack, what do we got? I've got a cocktail called the Unruly Revival. It's a fall riff off of the old fashioned. Woodenville, Applewood, Finnish, 100 proof bourbon. Apple Brandy from Clear Creek. Muscovado syrup infused with bay leaf. Vanilla infused aromatic bitters. And black lemon bitters with tobacco. Hey everybody, welcome to the show. Our guests tonight, Lloyd, Hansel, and Sarah Rosales. They're from Radiator Whiskey. Let's do this. What are we going to do? Just cheers? Is that it? Cilantro. Yeah, cilantro! All right. Okay, first off, the name of the place. You have a couple places. Yes. But the one, Radiator Whiskey. So in my mind, I think this has something to do with prohibition. It does. Does it really? Look at you. I'm so smart. Really smart. Don't tell me about it. Exactly right. So when we were trying to come up with a name, we didn't know where to name this place. And you know, you hit Google and we know we didn't want to be a speakeasy type of thing. We wanted it to be kind of a throwback to prohibition. So just doing web searches of prohibition type stuff. We found people made spirits in their radiators to hide it from the cops. That seems crazy to me. So I turned to Radiator Whiskey and we're like, done. Done. Done. What are you hiding from the cops? We're hiding nothing.   Is that something you have to hide from the cops?  I don't think you have to hide it from the cops. I hope not. I don't know. Yes, that is one of the things we're known for. Half a pig's head. It's quite the thing when it shows up on your table and the pig is looking at you. So it's half the head. It'll feed three or four people. And it's just a smoke. And the teeth are still in there. What? In the whole yard. People want to come and see the pig head and have it come to the table. It's in people's neighboring tables. They're like, what's that all the time?  That's absolutely true. Wait, is it really that there's just limited number of pig heads? There's only, we only have one smoker. We're a small place. So as many as that smoker will fit is as many as we can do and we sell out almost every night. So now, had you done other restaurants or other types of things before this? I had not. No. So what's your background? So I worked at the Boeing company for about 20, just shy of 20 years. Of course you did. Why not? I'm in Seattle. You're in Seattle, right? Yeah, I did that for almost 20 years and then had the opportunity to do the restaurant. And the business partner who owns another restaurant called the Hats in the Market, which is an unbelievable place. Like also, was your partner at Boeing as well? No. He was a fish thrower down in the market for years. Really? Yeah, he was kind of the guy. Yeah. And as a guy, I've known him since I think the seventh grade. Oh, wow. So we grew up in the same neighborhood, known him forever. And he threw fish forever down there. And then he took over a restaurant called Mats in the Market in Pike Place Market as well. Yeah, Pike Place as well. And then when the Space for Radiator came available, he's like, dude, I'm like a man. So you gave, how long were you at Boeing? 20 years. 20 years. Yeah. I'm going to go start a restaurant with pig heads and whiskey and, like, why? That's a good question. I think my wife still asks that question. Yeah, I want to know that too. Well, I think after, Boeing was great for the first 18 and a half years. Yeah. I still liked all the people I worked with. It was a fantastic place, but I don't know if you've ever seen the Boeing plants. It was these massive buildings and you sit in the middle of them with artificial light for 10 hours a day with no windows. I mean, there's no windows. You get no natural light for going on 20 years. Yeah.  You get the twitch. Exactly. Yeah. So why the restaurant? Is it because of your friend that you knew for a long time? He's called you up? Kind of. When he took over his first restaurant, he asked my wife and I to join him on that and he'd never run a restaurant. We'd never run a restaurant. You know, it's a lot of money, a big commitment. We're like, we're going to pass this time. Yeah. Even though I was like, I'm all in by my wife's side. No. And she was right. She was 100% right. But I'm like, hey, if you ever want to do this again, you know, hit us up and about four or five years later, I think it was, the space came available for radio to whiskey and I'm like, we're in. So where did the two of you meet? Was it in doing this and setting this up? Him and I? Yeah. Absolutely. Sarah was the diamond in the rough find at the Holiday Inn. It's right. What? Downtown Seattle. Yeah. Yeah. What were you doing at the Holiday Inn? Well, so I was at UW when I very first started bartending at the Holiday Inn. Okay. I'd never bartended before in my life. I'd done a lot of restaurant jobs. I'd been in the industry. Yeah. All, you know, all through my 20s and whatever. But Lauren had a bartender at the Holiday Inn, made horrible drinks for the first two to three years that I bartended or however long. And then started to get into the craft and started doing tons of research and then sitting in front of bartenders at bars like the zigzag and whatnot. And had a little kit that I used to keep underneath the bar. So in case anybody wanted to come in and get a real cocktail, I would be like, oh yeah, here, here, I've got some chartreuse right here. Let me. The Holiday Inn. Yeah, oh yeah. I love this so much. And I had a double-sided cocktail menu. One side of it was just like lemon drop style cocktails. On the other side was like nice and craft cocktails. Yeah. Dan Buggy had caught wind of me, came in, didn't tell me who he was. Now Dan was the business partner. He was the business partner. Yeah. Ordered a Manhattan, sat and chatted with me and then ordered a bartender's special. Yeah, yeah, yeah, yeah. Just said, make me whatever you want. And then he said, so I'm starting this new restaurant. What? Yeah, so that's how it happened. So he picked you up at a Holiday Inn. Yeah. To start the new restaurant. Yes. At a Holiday Inn. You're on board from the very beginning. Yeah. So you were before they opened the doors? Before we opened the doors. Oh yeah, yeah, yeah. I went in there and if you go in and the shelves on the back bar, I built those things. You built the shelves? Yeah. Our four original employees were Sarah, Tyler, Charlie, and Evan. And Evan. And Sarah, Tyler, and Charlie are still with us. Yeah. I could tell by the way you said Evan. And Evan. And Evan. You guys spit on the ground. Yeah. Now Evan's wonderful. We still have a picture of him on the wall. With angel wings actually. Yeah. You have angel wings coming out. Absolutely. All right. So radiator whiskey. Okay. What sort of like, what sort of mistakes have happened at Radiate? Wait, wait, wait, wait. You get to tell me. Yes. Yes. So I think one of the, this was one of my early, this was fairly early going in. And I'd come in, we opened at four. And I'd come in around five o'clock. And there was this calm around this, everyone, the whole staff. Everybody was just quiet. Something was wrong. Something was wrong. Your body senses kicking on. Everyone was just kind of, usually you walk in. It's everyone's kind of upbeat. And it's kind of, something was wrong. And I turned to, I'm like, what's going on? She's like, oh. So we were looking, you were trying to smoke? Our, our smoker gun broke. Our smoker gun broke. Okay. Yeah. Someone had the great idea to put in a pan. In the smoker. In the smoker.  Turn it off. We were open for business, by the way. Full. Restaurant's full. Wait, wait, what did you put in the pan? Whiskey. Because I, oh, so sorry. We have a smoke. Whiskey in a pan. We have a smoked maple fashion on our menu. On our menu. Okay, okay. Our smoker gun broke. You need to, you need to smoke. And let me just, let me just preface this by saying that we had a server who worked at a different restaurant. I won't name any names, but he said, why don't you just use the smoker? We had, we do it all the time at my other restaurant. Absolutely. Wait, wait, wait. It's the smoker for the pig. Yes. Yes. And, and the, and the other things that we smoke at retail. Okay. Fill the pan with whiskey. Put it in the smoker. Close the door. It was about five o'clock. Five o'clock. Wait, wait, wait, wait. Fill the pan with whiskey. Yes. And then put it into the smoker.  Oh, this is going to be amazing. Full restaurant. Was it 20 minutes later? About that. Yeah. The door. The door. Blows off the smoker. Boom. In the middle of, in the middle of service. In the middle of service. The best, the best part of that though was the entire restaurant jumped up and ran out. Oh no. But where the smoker is located, we have the smoker right here and there's bar seating right here. Right in front of the smoker. So like where this table is. Okay. And this is where the bar is. There was two guys at the bar. This is my favorite part of this. Who just thought that we were putting on a show for them. Yeah. The restaurant empties. They thought it was hilarious. They were just like, this is the best thing I've seen. I can't believe it. I was so glad I came to this restaurant. A bomb went off. In the middle of a packed restaurant. The door flew off the hinges. Yeah. Blew the door out. Wait, completely off? Yes. Completely. It was a bomb. I'm not kidding. How heavy is the door? Oh, it's heavy. Like an iron door. We had to get a whole new door for it. It's probably this wide and five feet high. Really? It's a metal. Just completely comes off the hinges. It happens when you put a can of whiskey in a smoker. This is like a cartoon. And then whiskey shot out everywhere and it was all flaming. Oh, because it's on fire. Flaming alcohol into the restaurant. And these two guys at the bar just sitting there laughing it up. They loved it. All right, so if you guys had like one piece of advice for somebody that's starting their own thing, they're completely scared. Honestly, I think I'm even asking for myself. They're terrified of like starting something and putting it together. What would you tell them? You mean as a business owner? Yeah, as a business owner or even like for you, you took the leap into something like that was unknown. It was the very beginning. It was unknown for me, but what I would say for people who are especially in the industry, I can't speak for anything else except for restaurant owners. Do not think that you can be a home cook and then start a restaurant. That's it. I mean, you have to have experience. You have to know how a restaurant works. You have to have years in this industry. You can't just say, wow, I know how to cook, right? I like to make drinks. I'm just going to go start a restaurant because you will not survive.  And you have to do it for a long time. Right. Just to figure it out. It doesn't work, right? Absolutely. And in that same vein, it's higher people that know how to cook. Know how to make great drinks. Know how to manage a restaurant and provide exceptional service. Like have a team. Like actual people that know better than you do on what you're putting together and make that happen. Like you don't have to do everything. No. Don't even try. Especially if you don't have the experience to do it because it won't work. You just don't know what does and what doesn't. I remember one of my college professors, economics professors, I remember one of the things he said in the opening day, first day of class, talking about going out and starting your career and this and that. And the number one thing he said is, don't open a bar. Don't open a bar. And he's right. Because I don't know what it is. The statistics are 90% of them fail. I think restaurants, more than anything else, because at least liquor doesn't go bad. True. I got you. But food does. I got you. I got you. I got you. It's been great. Awesome. Well, Lloyd, Sarah, thank you so much for being on the show. Yes. Thank you. Thanks for having the drinks. Of course. All the way through. Now it's the Rovina. Cheers. Thanks again. Thank you.  They've got all the tools and services to make you successful and even better, there are thousands of GoDaddy guides all over the world, some near you that will talk to you, that will have a back and forth with you to figure out what you can do to be better. So if you have taken the leap and you think you can inspire other people with your story, we'd love to hear it. And hey, hope to see you on the show.


Let's start off for those of us that are neophytes. What is the 211 system? Well, 211 is a national phone number that you can dial to get help with virtually any problem or issue that you're dealing with. So you're right. You call 911 for critical medical emergencies or those kinds of things. You call 211 for health and human service or mental health related needs or you need to be connected with services in the community. 211 is actually 96.5% covered in our country. So wherever you're standing, if you dial the 211 number from your phone, you're going to be connected with the 211 that's in your immediate community. So in a nutshell, 211 basically connects people who are in need with services that can help them. You dial 211, you're going to be connected with a professional counselor who is going to be empathetic, who is not going to judge, who is going to listen to you, who is going to help you figure out where you might have needs. The thing you called about and other things that might be going on with you or your family members, really just talking through whatever the issues are and making sure that you're connected with resources that are available in the community. It is anonymous. It is confidential. It is for anybody, including non-English speakers. All of us have the ability to do phone-based interpretation, and we encourage people to talk with us in whatever language they're most comfortable using. That is amazing.