Carcinoid Cancer Treatment

male speaker:okay? all right. dan, do you want to come up? dan kastner is the scientific director forthe division of intramural research at nhgri and he's with us today to give you a presentationabout the division. counsel has no direct oversight or responsibilityto the intramural research program but we think it's very appropriate that you get afull range in understanding of all of the kind of science that goes on under the nhgriand so dan's going to fill you in about the intramural program. male speaker:and we do this just, again, for new counsel.

we do this every couple-to-few years; we havea presentation by the scientific director to just sort of let you know what's happenedon the other part of the institute which has -- and i'm sure dan will describe -- has itsown external advisory group, the board of scientific counselors. so, again, this isas much as anything just for your orientation to other things going on with institute funds. male speaker:dan. dan kastner:all right. well thank you very much eric, and rudy [spelled phonetically]. and thankyou all for the opportunity to talk to you this morning. i realize that i have just halfan hour so i won't perseverate here. but in

any case really, the intramural program issomething that is near and dear to my heart and over the course of the next little bitwe will talk about seven different things. first of all i'll give you a little bit ofbackground with regard to intramural research at the nih in general, just in terms of howit operates. secondly, i'll give you a big picture view of the nhgri intramural researchprogram. thirdly, i'll give you a sampler of some recent scientific accomplishmentsbeyond what eric mentioned just a couple minutes ago. fourthly, i'll talk a little bit about thenhgri intramural research program as a genomic catalyst; as basically an organization thatwas developed, actually, at least in part

-- with the idea of francis collins back in1993 -- that really the intramural program of nhgri should be the engine that would drivethe infusion of genomic thinking and technology into the broader intramural program of thenih. fifthly, we'll talk a little bit about scientificreview of the nhgri intramural research program. sixth, i'll give you a little bit of an updatewith regard to our budget. and then, finally, we'll talk a bit about opportunities and challengesfor the future. all in 30 minutes. so, in any case, first of all, the distinctivefeatures of intramural nih. and these are things that i usually talk to the site visitorsabout when we begin our orientation for site visits and so those of you who have been tosite visits, perhaps, will recognize at least

this slide. so the first thing is that, in the intramuralnih there is really an institutional commitment to researchers over projects and so it's alittle bit more like the hughes institute than a grant-driven kind of environment. thereis a quadrennial, heavily retrospective review process and it varies from institute-to-instituteas to what percentage of the review actually is retrospective versus prospective. in nhgriit's about 50/50 in terms of retrospective and prospective. in some of the other institutesit's as much as 80/20 retrospective/prospective. thirdly, because of the fact that we havethis commitment to researchers and a quadrennial retrospective type of review, the intramuralprogram, perhaps, lends itself to long-term

studies that require stable funding and isa place where, at least to some extent, one can conduct high-risk, high-reward projectsthat would be difficult to do with typical arrow one funding mechanisms. there are alsospecialized resources in the intramural program and certainly the one that probably standsout the most is the clinical center of the nih. and we'll turn to that in just a moment. next there's a critical mass in certain areasand particularly in genomic medicine, i would say. in immunology, in structural biology,and in vaccine research there is very much a critical mass in terms of really excellencein the intramural program. one of the things that the intramural programwas specifically designed to do was to be

able to turn-on-a-dime that when there arepublic health emergencies like the ebola emergency or back in the 1980s the hiv crisis, thatsubstantial resources can be marshaled to study those areas and to make progress relativelyrapidly. next, it is the intellectual home for institutedirectors and extramural program staff and we really want to have a vibrant environmentwhere these people can have an interest in science. and then finally, it is, of course, closeto the seat of government and it's not unusual for senators or congress people to come tothe intramural program to see what's going on and we certainly want to have the bestpossible environment to show off to that.

this is just a picture of a clinical centerof the nih. it's a 234-bed hospital where patients can be admitted at no cost to themselvesor to the investigator who is admitting them. because of that it really does open the possibilityfor people to do research studies that are driven by the science. of course, all of thepatients have to come in on a irv-approved protocol. but still, it really does open thedoors, then, for a lot of intellectual freedom with regard to the clinical research. within the nhgri intramural program, justa brief overview of what it's all about. we have, right now, 22 tenured investigatorsand three tenured-track investigators. naturally we are in the process of converting one ofour physician-scientist development program

members into a tenured-track position andso this will soon become four tenure-track investigators. three of our tenured investigatorsare members of the national academy of medicine and two are members of the national academyof sciences. we have 14 associate investigators. the associate investigators are like the researchtrack at academic medical centers. we have nine adjunct investigators whose primary appointmentis with other institutes but who collaborate with the nhgri. as i mentioned, we have one member of thephysician-scientist development program which is a program that les biesecker developeda number of years ago to help individuals who have finished their clinical trainingget sufficient research background that they

can compete for tenure-track positions. we currently have 513 personnel within theintramural program. this doesn't include contractors. with contractors it's a little above 600.and after a reorganization that we did in late 2013, we now have nine branches. andi will illustrate the organizational structure in the next slide. we have eight cores. the nih intramural sequencingprogram sider, which eric alluded to in his talk, and then the undiagnosed diseases program.the fiscal year of 2016 budget for the intramural program is $105.4 million so it representsabout 20 percent of the overall funding of the nhgri. and it's a far-flung operationwith seven buildings on-campus and two off-campus.

and that's just, in part, a product of thefact that the nhgri intramural program is young, relative to some of the other intramuralprograms and so we've basically gotten space wherever we can as we've grown. this is just the organizational chart of theintramural program. a number of individuals are relatively new in their positions. sopaul liu, our deputy scientific director, who eric alluded to at the end of his talk,is the at least relatively new deputy scientific director. he replaced andy baxevanis who tooka nih-wide intramural role with regard to computational biology. and paul replaced him. we have three new branch chiefs who were appointedat the time of the reorganization and they

are charles rotimi, julie segre, and pam schwartzberg.and then, laura koehly is a relatively new acting chief of the social and behavioralresearch. the intramural program of the nhgri does tendto focus more on the dimensions of the density plot from the iconic 2011 figure in nature.in basically understanding the biology of disease and advancing the science of medicineare the two areas that really are the major focus of the intramural program and that'sat least, in part, due to the accessibility of the clinical center. and so there is moreof a clinical bent [spelled phonetically] to what's going on in the nhgri intramuralprogram than, perhaps, extramurally. although, as eric has said, certainly the intramuralprogram has sort of blazed the way in terms

of this and the extramural program, i think,is now very much orienting in this direction. just highlighting a few of the things thathave gone on in the intramural program over the last several years. one of them that reallydoes highlight the ability to focus on a particular disease for a long time and to learn somethingabout it and to make great headway is les biesecker's project on proteus syndrome. andles actually began studying proteus syndrome 20 years ago back in 1996 with a natural historyprotocol. that protocol allowed for the delineation of a number of sub-phenotypes, eventually,with the advent of next gen sequencing. les was able to demonstrate that, in fact, proteussyndrome is caused by activating mutations -- mosaic activating mutations -- in akt1.and, at this point, les actually has begun

a targeted treatment protocol for proteussyndrome. so this is really an example of where, over the course of a 20-year periodof time, with persistence and intensive study, we've gone from the delineation of the clinicalphenotypes onto a treatment protocol. another example of this sort of thing is thework of chuck venditti, who was a member of -- initially a member of the physician-scientistdevelopment program and during his tenure track he became one of the world's expertsin organic acidurias and, in fact, accrued over the course of time, a very large cohortof patients with different organic acidurias. and this is just an excerpt from a paper thathe published in nature genetics back in 2011 describing a new gene that's the cause ofcombined malonic and methylmalonic aciduria.

moving on to the social and behavioral researchbranch, philip shaw, who is one of our new tenure-track, or relatively new tenure-trackinvestigators, has actually, at this point, accrued the largest cohort of patients withadhd who have undergone serial mri scans. and so basically what philip is trying todo is to define a biologic phenotype rather than just going based on clinical phenotypingof patients. and so this actually illustrates some of the data that philip has garneredbasically showing the connectome tracks within the brain that turn out to be highly heritableand, in fact, that correlate with adhd. and so just as we've learned recently that schizophreniais a disorder in which there is excessive pruning of certain synapses, in the case ofadhd there is a deficiency in terms of pruning

of certain synapses over the course of adolescentdevelopment. another example of a focused examination ofa particular group of patients that has led to great insight is ellen sidransky's workon gaucher's disease and the observation that, in fact, mutations and glucocerebrosidasepredispose to parkinson disease. and she has gone on, as illustrated in this slide, tomake ips cell lines from patients that have glucocerebrosidase mutations and have developedparkinson disease and has screened these cell lines with a compound from the ncats fromthe national center for -- whatever. but, anyway, the ncgc and -- [laughter]

-- chemical genomics. and has identified acompound that actually has an effect in terms of the trafficking of glucocerebrosidase inthe cells and thereby the accumulation of alpha synuclein. and so this actually doesrepresent, then, a possible therapeutic modality for parkinson disease going forward. this slide illustrates yet another interactionbetween one of our intramural investigators. this being joan bailey-wilson, with a veryproductive collaboration with steve wang, who's a gastroenterologist, an niddk, identifyinga gene that predisposes to small intestinal carcinoid tumors. and then, on this slide from pam schwartzberg'sgroup, the identification of germ-line mutations

and pi3 kinase catalytic subunit as leadingto an immunodeficiency decision. and basically what happens in this condition is that becauseof activating mutations in pi3 kinase there's actually an exhaustion of certain subsetsof t-cells leading to an immunodeficiency. from my own group, we described a conditiona couple of years ago that we call dada2, which is deficiency of the adenosine deaminasetype 2. now, as some you may know, adenosine deaminase type 1, or just ada, is the enzymethat's deficient in many patients with severe combined immunodeficiency disease. in thisparticular case, the phenotype was one in which patients were referred to us with recurrentfevers and strokes. and these patients, in fact, had multiple lacunar strokes in thedeep nuclei of the brain, as illustrated here

on these mris. these patients have mutationsand adenosine deaminase 2. this figure here actually shows polyarteritisnodosa, which is another phenotype that can be associated with this condition. and, inany case, having this cohort of patients and having some detailed phenotypic informationabout these patients and linking up with another group in israel that had a cohort of patientswith the pan form of dada2, allowed us to at least start thinking about treatment forthis condition. and so, in the cohort of patients that wehave, they had cumulatively 44 strokes over 1,064 patient months. so roughly one strokeevery two years. because of the fact that we saw tumor necrosis factor in the cardiovascularareas in these patients, we started on our

protocol tnf inhibition in these patientsand so in 323 follow-up patient months -- same patients -- 12 patients, zero strokes. andso, really, this is an example of how the intensive study in a clinical center doesallow one to learn something that can do some good for patients. and then, finally, another paper that we hadjust come out last week in the new england journal deals with vibratory urticaria. sovibratory urticaria is a condition in which if you take someone's arm and put it on alaboratory vortex, they will actually develop a hive on their arm. and this is illustratedhere on a control individual before challenge and after challenge. no difference in theappearance of the arm, whereas in this patient,

you can see the development of the hive inducedby stimulation. and this is caused, actually, by mutations in a gene, adgre2, which is anovel -- encodes a novel protein which is actually a mechanosensor on the surfaces ofmass cells that actually can detect a vibration and if these particular patients happen tohave a mutation that leads to increased sensitivity to vibratory stimuli. so, in any case, anotherinteresting development. this slide simply illustrates some of thework that francis collin's group is doing with regard to the epigenome in type 2 diabetes.and one of the things that they have found is that in islet cells, actually, there isa chromatin state that is specific to the islet itself and a "stretch enhancer," asfrancis' group calls it, which actually turns

on the glucokinase gene in islet cells. another interesting development which is comingout, i believe this week, is a paper from laura elnitski's group which shows that thishypermethylation of the znf154 promoter in solid tumors. and that this actually couldbe the basis for a blood test for certain solid tumors. here, turning to the canine side of things,is actually something from elaine ostrander's group that deals with a venereal tumor thatcan be transmitted between dogs. and basically this image just shows the chromosomal translocationsthat occur in these venereal tumors. and basically in these tumors there are a number of rearrangements-- a number of mutations that actually are

in immune-related gene that render these tumorsundetectable, or at least very difficult to be detected by the immune system. work from bill pavan's group. looking at sox10actually shows a difference in terms of the activation mode of sox10 in pigmentation whereit is activated versus in melanoma where it is inactivated. and then, work from my own group, lookingat pyrin, the protein that is mutated in familial mediterranean fever. this is something thatwe have under review at nature. basically showing that, in fact, pyrin is controlledby rho gtpases. and, in fact, there are certain bacterial toxins which poison rhoa, one ofthe rho gtpases. and that this is what actually

is being sensed and what regulates the pyrininflammasome. this mechanism, which is known as the guardmechanism for regulating innate immunity, is something that, at least up until now,has only been seen in plants. and so it's, at least, the first example of where thisguard mechanism may be involved in humans. so, anyway, then turning to the impact ofthe nhgri irp on the nih campus and beyond just a few things that i will briefly mention. first of all, many of our investigators, actuallyour experts, in particular diseases that then can be referral centers for investigators'other places. this is just an illustration of max muenke's work with muenke syndrome,which is a form of craniosynostosis. and,

essentially just illustrating a recent reviewof his group on this topic. but there are many intramural investigators that essentiallyserve as experts in these diseases. next-gen sequencing at nisc is another areawhere the nhgri intramural program has really had a major impact. and this graph simplyshows that over the course of the last five years that the number of samples that nischas sequenced has gone up by an order of magnitude. and that if one looks at the samples, at leastthe investigators who have submitted the samples -- because this is something that is availableto investigators in other institutes -- that in fact, the majority of samples are fromother institutes and so this really does subserve a very important function at the nih.

recently, les biesecker and jim mullikin spearheadedthe clinical center genomics opportunity project, which is a project that allows investigatorsfrom other institutes to do whole-exome sequencing for medically important diseases. and so thisis another area where nhgri is taking a lead in terms of genomic analysis in the intramuralprogram. of course, les biesekcer's clinseq programis another example of this in which essentially the basis of genomic medicine has really beendefined. and just some examples here of some of the papers that have resulted from that. and then, of course, as eric alluded to, theundiagnosed diseases network, which is really an outgrowth of the undiagnosed diseases program,which bill gahl established in the intramural

program back in 2008 which has now reallygrown into something that has had major impact across the research community. and, in connectionwith that, our social and behavioral research branch has really spearheaded the analysisof a lot of the secondary findings in the undiagnosed disease program and in the clinseqprogram. and so that also has had, i think, a major impact. software has been made available through anumber of our intramural investigators and, just for lack of time, i won't go throughall of those. we have the current topics in genome analysis series, which is now goneon for 12 years. and actually, andy baxevanis and eric have had a leadership role in thatcourse. and you can see here that attesting

to its impact, there have been 740,000 youtubeviews of posted lectures to date. then moving to other areas of impact, i'lljust mention charles rotimi's role in terms of the h3africa work, julie segre's work definingthe landscape of bacterial and fungal colonization of humans -- her pioneering work, with regardto tracing hospital-acquired antibiotic resistant organisms, and then a recent paper, or setor papers, from john burgess basically laying out a strain h1n1 for zebrafish, crispr/cas9immunogenesis, and a targeted immunogenesis of 162 different locine [spelled phonetically]and then, finally, the compilation of all of the crispr/cas mutations that are at leastexpansive literature as of the last -- at the end of last year. science in the intramural program is evaluatedby a ward of scientific counselors, a set

of outside experts. john atkinson is currentlythe chair of our board of scientific counselors. the three members who are highlighted in yelloware our newest members, lucille adams-campbell, an epidemiologist from georgetown, jeff murray,who many of you know from the aids foundation, and tim townes from uab, a bio-chemist. the investigators in the program are ratedon a scale of outstanding, excellent, and very good. and at least over the last fouryears, 27 have been rated as fully outstanding out of the 39, which is approximately 70 percent. just to turn to the budget -- and i see thatwe're nearly out of time -- the budget this year, as i mentioned is $105 million a year.it has been relatively flat over the last

several years and so when i took this positionas scientific director in 2010, it was $104 million. it did go down and it's now beginningto go up. on average, our investigators have had a 16 percent reduction in overall budgetover this period of time. we have recruited two new tenure-track investigatorsthat i will just mention. adam phillipi [spelled phonetically], a bioinformatician from thenational biodefense analysis and counter measures center that's a part of the department ofhomeland security. and adam was actually in the part of the department of homeland securitythat would screen the white powder that people would receive in the mail, or might receivein the mail, determining whether or not it was some sort of a pathogen. he's an expertin algorithm development and single molecule

sequencing. and then, finally, peter mcguire, who's beingpromoted from our physician-scientist development program to a tenure-track position. and thisimage just shows the metabolomics work that he's doing, basically showing that in a principlecomponent analysis of metabolism, that metabolites that in point-of-fact one can separate subsetsof t1 [inaudible]. so, in terms of challenges for the future,continued faculty recruitment is one of them. expanded engagement with other institutes;a seamless integration of bioinformatics with bench science. and we're right now renovatingspace in one of our buildings to bring together adam phillipi with two other individuals,julie segre and laura elnitski towards a molecular

taxonomy of human disease and so that, basicallywe're looking to do more of what i've described up until now. that is to say, identify monogenicdiseased genes. and then the 10,000 exome recall cohort is basically developing a cohortof patients at the clinical center who will be fully genotyped in where we can call themback if they have interesting genotypes for deep phenotypes. so i think with that i'll call it to a close.i did actually make it in the allotted time. and if you have any questions, i'll try toanswer them. thanks a lot. male speaker:we can certainly take some time for questions. or comments? val [spelled phonetically]?

male speaker:i guess i have a couple of budgetary questions. so in the $105 million i think you mentionedthat investigators could have patients evaluated -- dan kastner:yes. male speaker:-- internally for no cost? dan kastner:so the cost of that, actually, and i didn't have time to go through that aspect of thebudget. but we are actually charged -- each of the institutes that sees patients in theclinical center -- we are charged a so-called school tax, which is 14 percent of our intramuralbudget so that since we have an approximately

$100 million budget, that means that, in essence,we spend about $14 million a year. so it's, quote-unquote, at "no cost," but we're paying$14 million a year to have that privilege of being able to do that. male speaker:yeah. so that $14 million is part of the 105 or in addition? dan kastner:that's correct. that's correct. yeah. male speaker:and so that -- you pay that based on your budget, not based on the number of patientsthat you evaluate? dan kastner:that's right. and so we have --

male speaker:do you have any idea of whether you're losing money or you're making money based on thenumber of patients that you're seeing? dan kastner:yeah. well, right now nhgri is a little bit on the side of losing money. so that we actuallycould -- it would be good if we could see more patients at the clinical center in orderto get our monies. male speaker:what about with the nisc? what's the finances of that? dan kastner:so the nisc, it's also part of the $105 million. and we spend approximately $7 million a yearon nisc and that basically allows us to maintain

the sequencers; maintain at least some bioinformaticanalysis of the sequence. we do have a program within the intramuralnhgri where people can apply for competitive grants, basically, or competitive fundingof sequencing where people can either have large flagship projects or smaller pilot projectsthat if they compete well in this process they would be able to do. and then, as partof this clinical center of genomics opportunity, we do provide funding for 1,000 exomes forother investigators. that's actually a joint project with michael gottesman's office, thedeputy director for intramural research, who basically is paying half of the cost of thatfor investigators in other institutes. male speaker:yeah. so you might not be responsible for

the answer to this but, so that $7 millionis also part of the 105? dan kastner:that's correct. yeah. male speaker:and you know how competitive you are with the commercial sequencing pricewise? dan kastner:well. yes. we -- we are relatively competitive. right now to charge -- if we charge intramuralinvestigators within nhgri, the cost is about $500 in exome. male speaker:very good. thanks. male speaker:the other thing -- val -- the other subtle

thing worth pointing out about that is thata lot of what they do is be preservers. i mean, and so people will vote with their feet.i mean, some people do go elsewhere but the big advantage of having it done by them isat least some amount of analysis that comes for free and by colleagues like, you know,jim mullikin and others and [unintelligible] and others in that group. and so the valueadded is the analysis by other members of the faculty. male speaker:thanks. male speaker:yeah. male speaker:so first thank you for the overview. could

you say something about the 10,000 individualrecall cohort? i was not aware of that activity. how you were doing your recruitment, whatthe goal is, and -- dan kastner:well -- male speaker:-- and you mentioned also the diversity within that group. dan kastner:yeah. so, right now it's just in its early stages. oh, sorry. right now it's in its earlystages. it's sort of clinseq on steroids, you could say so clinseq is certainly -- isthe -- the core of that. but patients from other institutes are being incorporated intothis and probably will be something that will

take a year or two to accrue all of the patientsfor this. and the idea is that if we have a cohort of individuals, where we have deepgenomic information, then we can, if there are investigators at the nih or elsewhere,who are interested in the phenotype that would be associated with a given genotype, thatthen we could call them back to the clinical center for deep phenotyping at the clinicalcenter. male speaker:anything about the ethnic diversity in the group? and you answered part of my questionso these are patients ascertained through a condition from another investigator -- dan kastner:that's correct. that's correct.

male speaker:-- and somehow you enroll them in this? dan kastner:so right now, at least in clinseq, there are a number of patients who are african american.les has been specifically trying to expand the diversity of the clinseq cohort becauseof that but it's a work in progress in terms of that. female speaker:i just want to follow-up on that -- that comment because when you said, "clinseq on steroids"-- because clinseq is volunteers. right? i mean, whereas the clinical center -- and ijust conferred with my colleague. dan kastner:so it's probably [inaudible].

female speaker:totally. yeah. but -- but it seemed to be a very, very different set of parameters thatyou're first, you know, characterized in the population and, in fact, maybe -- i mean thepeople who come there are more selected for rare conditions but they won't have the sameselection bias that you would have from a volunteer cohort. dan kastner:that's true and so one of the things that it's -- is at least in the works, althoughit has not been formalized yet, is that les, and richard seagull [spelled phonetically]in nmis are establishing a relationship with inova fairfax and they actually have beendoing a -- okay it's a -- okay, that is a

hospital in northern virginia. and they actuallyhave been doing whole genome sequencing on just individuals who come through that hospital.in a lot of cases it's through the obstetrics department and so it's just normal deliveries.and they have actually 8,000 individuals who have had whole genome sequencing where, infact, that might shift the distribution more towards the type of individual that you'retalking about of people that are just from the population. male speaker:dan [spelled phonetically]? male speaker:yes. so thank you for that summary. i just have a -- i have two questions and it justshows my naivety about the intramural program.

what does tenure mean? i know what tenuremeans at my place but i'm not sure what tenure means here. that was one question. and then the other was that so the introductionis, sort of, high-risk, high-reward, a long-term investment in programs that couldn't be doneelsewhere and you showed some beautiful examples of science. i'm not sure i agree that a lotof it couldn't be done elsewhere and so can you talk a little bit about the things thatthe intramural program does that, you know, that are examples of things that -- that reallyare, you know, such long-term, high-risk, high-reward investments or the turning-on-a-dime,that, you know, is there anything going on in -- in not -- ebola was last year's news.

male speaker:zika, for example, that -- that, you know, if you try to do it through ordinary grantmechanism would take a year-and-a-half before anybody got a dollar to start to work on it.so could you talk a little bit about those things? dan kastner:yeah. so, with regard to tenure, first of all. so tenure is something that, as opposedto in most academic institutions in which one can be tenured and if you don't have grantfunding then it's going to be very difficult to maintain your research program. in fact,in the intramural program, tenure does involve a long-term commitment to an individual aslong as they maintain their productivity as

judged by reviews by the board of scientificcounselors. and that's really the crux of the matter. the key is that people have tomaintain their productivity in order to maintain their funding. but if one does maintain that,then it is a commitment, in a way, that one doesn't usually see in a university or academichealth center. so that's with regard to tenure. now with regard to programs that people doin the intramural program that are high-risk, high-reward or things that can't be done otherplaces, well, i suppose that, you know, one can say that nearly anything if one focusesenough on it that one could do it in another place. i do think that the examples of someof the cohorts of patients with rare diseases where in point-of-fact it would be very difficultto maintain those cohorts over a long period

of time, as i mentioned with les biesecker'swork, for example, on proteus syndrome, is something that, sure, one could do it somewhereelse. it's not as if it couldn't be done anywhere else. but certainly those kinds of projectsare projects that would be hard to maintain any way in another -- in another setting. as far as turning-on-a-dime is concerned,certainly right now there is an initiative in niid to start tackling zika virus and sothere are such things as that. certainly last year ebola, as you may know, there were ebolapatients that were at the clinical center of the nih and certainly in the 1980s withthe beginning of the hiv epidemic there was a lot that was being done in the intramuralprogram. but, you know, by and large, i would

have to say that the most important thingwith regard to intramural science is excellence and that certainly is the thing that in ourreview process is really, really critical. male speaker:anything else? okay. so, thank you, dan. it was great. and,rudy, you're going to instruct us. male speaker:all right. so why don't we try to be back by 1:15 to resume the open session. there'sa cafeteria one floor up that i recommend for lunch. you can bring your food back downhere if you like. if there aren't tables available you can also go upstairs on the fourth floorand visit with staff. you can leave your computers. someone willbe in the room all the time. i would advise

you take personal wallets. male speaker:okay. male speaker:we'll see you at 1:15. [end of transcript]