Good afternoon everybody. Thank you for coming here and it's so nice to see so many of you here. Before Helen introduced the speakers, I would like to make a few announcements. This event is being sponsored by the Biospecimen Interest Group, and it's supported by the Office of Disease Research, and the Office of Biospecimens and Biorepositories Research at the NCI. If you would like to get involved in this group, please contact us or log on to our website. I would like to mention also that our next presentation will be in January, and we are soliciting names for future speakers, so if you have any suggestions, please let us know. Also, I would like to let you know that we are lucky to be the first one to be using the new state-of-the-art equipment that was installed in this auditorium. Today we have the privilege and the honor to have three outstanding speakers presenting an extraordinary program on the hand-diagnosed disease program, which Helen is going to introduce to you. Alright, thanks. I add my thanks to your coming today, and I just want to take a moment and thank Yaffa for organizing this. I'm only an accessory here. Today she has done all the work to make this happen today. And so we're not going to read lengthy bios this afternoon, but just tell you that the speakers today are first Steve Groff, the Director of the Office of Rare Disease Research at the NIH, John Gallin, Director of the NIH Clinical Center, and William Gall, Clinical Director of the NHGRI and Director for the Undiagnosed Disease Program. So Dr. Groff will start us off. Thank you, Helen and Yaffa, for this opportunity to present the program that has started maybe a little bit over a year ago. But before I begin, I do want to first thank the staff here at the Clinical Center. I think maybe sometimes you don't hear the comments that come in from the people, especially in the rare diseases community, but I really can say without any question that the first question I get when I go and I meet with the patient advocacy groups and their scientific and medical advisors is, how do we get a study started at NIH? How do we get into the NIH system? So I think you can see the esteem that so many people in the rare disease community really hold for you and the programs that you represent and the research that you conduct here at the NIH. And it really is a tremendous testimony to the dedication to all the rare diseases that you have become known for. And we certainly appreciate the efforts of so many of the individuals who have helped with the program as we've initiated here at the Clinical Center. And so I'll just really give you a little bit of the background and then we'll turn it over to the more experienced clinicians and activities that we've been involved with. But I do want to thank the Biospecimens Interest Group that invited us and have participated in developing the whole program. So Yaffa and Helen, thank you again. It's a privilege and honor to express this program to the NIH community because it has been one of a tremendous amount of public interest and I think Bill will tell you the level of interest that we've faced and that they've faced within the program of screening patients and physicians who have patients who would like to come here. Just some background information. First, as far as getting the diagnosis or the diagnostic odyssey that we talk about particularly for the rare diseases where so many times the symptoms do not manifest themselves at one time, they're going to carry over a number of years maybe several decades until we really get the full picture of a disease. But back in 1989 when there was a National Commission on Orphan Disease and then this study was replicated in 2002 by the National Organization for Rare Disorders, we did some patient surveys and you can see there are the numbers that time to diagnosis and it's that greater than five years that had us really concerned as far as taking that long to actually obtain the diagnosis. And I think all of us can understand the frustrations and the anxieties that go with not having a diagnosis not knowing what we have, what are the outcomes that we can even think about. So when you start applying this to a pretty large population you see that there are a good number of people who spend many, many years trying to obtain the diagnosis. We have what we call the genetic and rare disease information center that we cosponsor our office, the Office of Rare Diseases Research with the National Human Genome Research Institute. And after about 10,000 inquiries we went back over a three-year period looking at the inquiries that we received at the information center and approximately 6% of the request for information related to undiagnosed diseases. So you can see that is a very, very large problem that we're looking at it's just we don't hear about it very often. In 2000, the NIH and our office published a report of a special emphasis panel on the coordination of rare diseases research and in that we talked about forming specialized centers of research and diagnosis. Unfortunately, when we were looking at this when we implemented our rare disease clinical research network we didn't focus on the diagnosis, we really focused on research, natural history studies, training of the next generation of physicians and then the active role of patient advocacy groups as well as doing clinical trials of the rare diseases. So we never really got into developing the specialized centers and we thought what we'd like to do is really get a little bit of experience here at the NIH. And so what we're really working towards is a better characterization and establishing diagnostic criteria for the rare diseases. And one of the ways that we do within our office and we try to extend this to all of the institutes and many of the intramural research program and investigators here in the clinical center have taken advantage of the program to put together scientific conferences on specific rare diseases or a group of rare disorders. So if you have an interest and you haven't heard about our scientific conference program please contact the office to send a quick note and we'll start talking to you about a conference and everything that you can do and how it all works. So we're happy to help with this. We've seen in recent years this expansion of newborn screening programs here in the United States and we think that this is going to continue to grow. I believe there are about 29 disorders now that are screened in the States here in the United States and we think that number is going to grow. Our program is also focused on the development of genetic diagnostic tests that should be accompanied by appropriate counseling and information to go back to the patient and families as well as to the practitioner. But we have a pilot project that actually started here in the clinical center with Bill Gaul and other investigators that we try to figure out a way to develop genetic tests and to move them out of the research laboratory into a CLIA-certified laboratory. So we've had a nice program and again we do make resources available. If you're in the gene discovery mode and you think that there is some clinical significance of what we're looking at as far as the diagnosis and other information that should be made available to the patients and the families, we'll help put together a genetic test and develop the information that will accompany that test. So again please just contact the office and we'll work together on that. But what we're dealing with really, with a program such as this, there's a tremendous amount of interest in this program. I think we're developing truly a global approach to rare diseases as more and more nations are coming on board with a focus on rare diseases. For so many years it seemed like the United States was the only country working in the rare disease area. Then in 1999 the European Union passed their legislation and so we've had a tremendous amount of effort. There should be a good number of collaborations with the European Union investigators in individual countries, so it's growing. The program itself, we would like to see it grow into more, and maybe Bill will talk about this or John about expanding into more the intramural research program. Most of the patients are being seen by a small number of investigators, but I think we'd like to see how this could be extended into other protocols and new protocols and the clinics here at the clinical center. At some point if additional resources were ever made available, and that's really money, we'd like to expand this into the extramural research program and use the clinical center here as a hub of activities that we could perhaps extend this out to a lot of the extramural research community. We have a very large clinical and translational science awards program, general clinical research centers that are a very, very fertile ground for introducing a program like this and our rare disease clinical research network is also another area that we think we could extend this and expand the initiative, so it's something we'd like to look at. Again, as I mentioned, there's a tremendous interest in the program throughout the world, and again, when I do go and speak with partners throughout the world, this is probably the number one area of interest how's the undiagnosed diseases program? How's it working? Is it really functioning? Are you seeing patients and what are the results? And so the partnerships are available. I think it's just a matter of us figuring out some way how we can really link up with them. There's been some proposed legislation that would develop a national undiagnosed diseases registry, and that has some complications. That's still in the hopper, but we're not sure where it's going, but it is certainly an area of interest as we continue to watch it to see exactly what they're going to ask us to produce. And throughout all of this, we have seen the increase, and many of you probably have observed the continued involvement of patient advocacy groups as research partners, and two new groups have started up. One is INOD in need of diagnosis, and the other is SWAN, the Symptoms Without a Name. And again, as I mentioned, these are people who've lived for many years without a diagnosis and named to their disease. They know most of them are not really good diseases. They're not doing well, but they've devoted their energy to try to bring an emphasis to obtaining diagnosis for a lot more patients. So with that, I will end, and I'm going to turn it over to Dr. John Gallin, who is the director of the Clinical Center. I'll see if I can get the slides. We may need some help finding John's slides. Okay. Okay. Are you getting it from back there? Here we go. Thank you very much, and John, we'll turn it over to you and then to Bill. Is that you? Okay, thank you very much. It's a pleasure to be here, and I want to thank first the Office of Rare Diseases for sponsoring the whole program of the Undiagnosed Disease Program, and specifically I want to thank the Special Interest Group for hosting this session today. I'm just going to spend a few minutes reminding you what kind of facility we have here and why this makes a special home, and then we'll turn it over to Dr. Gall, who's going to really provide the excitement for today. So what is the vision of the Clinical Center? In case you don't know, it's very simple. As America's research hospital, we will lead the global effort in training today's investigators in discovering tomorrow's cures. Now, we spent a lot of time writing this sentence, believe it or not, and things like America's is a key word, and our hope is that as time evolves, the facility will transform from not only a national hospital for patients, but also an institution that serves investigators both here at the Clinical Center and across the nation more so than it has even in the past, and that particularly relates to the comments Dr. Groff just made. So we opened, you know, in 1953, and since then we've seen more than 350,000 patients, and about half of them have been patients with rare diseases. Our new hospital opened in 2005. Currently we have 234 beds open. There are about 1,850 people who work for the Clinical Center, and I should add that it's about 4,000 people who work for the 17 different institutes that use the Clinical Center. So in these walls there's about 6,000 people working, and my hope is that they all work well together in my senses that they do. Of those people there's about 1,220 credentialed physicians, which is a rather remarkable number for 234 beds. I don't think you'll find that anywhere in the world. The engine that drives this place are the clinical protocols, and there are 1,450 active clinical protocols, and the budget for this year is $362.3 million. So our nurses say there's no other hospital like it. So what makes this place different? Well, as you all know, every patient is enrolled on a protocol. Care is free. Our nurses are very highly educated. Every one of them is a registered nurse. About 15% have a master's degree and about 5% have PhDs. The hospital is embedded in an environment with research labs surrounding it with some of the world's greatest investigators. Our theme is often first in human and clinical trials. We can do long-term high intellectual and economic risk studies. Because we don't write grants, we can respond rapidly to public health emergencies as we have done in the past, for example, in AIDS and in the SARS epidemic. And we have these unique cohorts of patients with rare diseases. So we've had a long tradition of studying rare diseases and patients with unknown diagnosis. So what's new with this undiagnosed disease program? Well, from my perspective, there are two major things that are new. First of all, there's a call for undiagnosed diseases with no phenotype restrictions. So we're inviting anybody who has an unexplained problem to make an inquiry. The second is that really, for the first time, at least since I've been here, a multidisciplinary approach is given to every patient. And this is shown by this list of consultants, which you're not supposed to read, but be impressed by the number. And so although Dr. Groff said there's relatively few people who are involved in this program, I think it's a very large, robust group representing almost all the different components of the NIH. But indeed, it could be bigger, and we hope it gets bigger over time. So what does the clinical center do? Well, we have an office of patient recruitment and public liaison, which Triage's patient calls. And since May of 2008, there's been about 1,700 inquiries, and every patient receives a preliminary screening. All the clinical center departments are primed to be helpful, and I think most of them have been key collaborators, but particularly our general medicine and pediatrics consult services, among others. We have a very large amount of outside inquiries about this program. You've read about it in nature. You've read about it in the New York Times, and you'll be hearing and reading about it more. And the communications staff from both the clinical center and predominantly the Human Genome Institute, as well as the NIH in general, have been very engaged in trying to help the public understand better what we do. The clinical center obviously provides a certain amount of space and supplies and special resources, and it's really the special resources that I think make this such a marvelous facility, and these resources have evolved because of our long tradition of phenotyping patients. So let me just, in one slide, showed you what I think are some highlights. We have a brand new GMP facility that's going to open in a few weeks here on the first floor for making candidate drugs. This is a fabulous resource that can help once the diagnosis is made, and new therapeutic strategies are contemplated when industry is not capable of interest or interested in helping making a candidate drug. We have a phenomenal amount of imaging equipment in this facility working closely with the NMR Center. There are over 27 MRI machines, for example, in this hospital, some of which serve animals, but the NMR Center is a facility to make new machines. A new 7 Tesla machine is about to be unveiled for clinical use, and we have multimodality, minimally invasive procedural suites, rather unique for the country. We have a biomechanics lab and the rehab medicine movement for testing and assessing movement, which late in chance group runs. Our blood bank is phenomenal in terms of helping prepare special kinds of cells for research purposes, both in the lab and in the clinic. We're now priming up to be able to do stem cell therapy when the investigators want to do that. And the phenotyping capability includes the metabolic suite for originally designed to assess obesity, but is available for testing. Wasting syndromes or any syndrome where you want to characterize the metabolic state of the patient with great precision. We also have some IT tools, and one I want to mention, and I'm going to end my comments with, is the Biomedical Translational Research Information System, or BETRAS, which Jim Semino has been building. And what is BETRAS? Well, it's a data and tissue repository, and in view of the interest of this interest group, I wanted to show you in one slide what it does. So from the clinical center, there's input into this system from the laboratory, the pharmacy, the imaging facilities, the CRIS system, the old-miss system, and from all the different institutes, they will be depositing whatever they want to deposit into this system that relates to patients. In the future, the CTSA network we hope will also contribute to this system, and we will be taking all the biospecimens and tissue information that's available at NIH, and I am told there's over 30 million specimens out there in freezers and things all over the place. Our goal is to eventually have all that information linked into this system. And so what we hope in the future is that additional institute research data and images will be added every year. The addition of the stored sample data, which comes from these patients with rare diseases, will allow investigators to search samples along with related clinical research data. So you'll have tissue information, you'll have clinical information, you'll have phenotyping information, genetic information, et cetera, all available in one place, and hopefully this will be a valuable resource to the community. And finally, as we begin to partner with the extramural community, our dream is that this kind of a system will become a national resource containing a vast amount of information that will enable hypothesis generation, hypothesis testing, before even going and doing experiments. So if you're interested in Beatrice and it's just been unveiled and become activated, you can learn more about it at this site. So those are my comments, and now I'd like to introduce Dr. Golf who's going to tell you about what's happening in this clinic. Well, thanks very much. I want to thank the Special Interest Group for the last specimens for their invitation, and John and Steve, especially my institute, but most of all, all of you who have contributed to this program so much. And if there's one message I want to send out to all of you, it's that we have cases up here that have not been fully explored, and if any of you are interested, I would like you to come up to us and tell us your interests, your specialty area, and if you want to pursue any of these disorders, please do because they still remain mysteries and we can use all the help we can get. So, I guess it's this one. Let me do it. All right, I'll use the bottom one. I'm fine. Yeah, that's what I was hitting. So this started with the Office of Rare Disease, getting all sorts of inquiries that really couldn't be answered, and Steve mentioned that already. But in addition, there was a retreat in 2007 in which the directors of the ICs thought of ways in which to sort of enhance or rejuvenate the clinical center. One of those ways was to recreate the fascinoma clinics of the 60s and 70s. You'll probably recall that most of the leadership of the NIH is now in the members of the second half century club, so they remember back to the 60s and 70s when they did this themselves, and I think they remembered that fondly, so they wanted to do that. And so we have the goals of the program to assist patients come to a diagnosis, but also discover new diseases that will reveal something to us about biochemistry, about pathways, about cell biology. And I'd like to show you today about how we're moving towards some of those goals. The way this program works is that we receive medical records and also a summary letter from the physician. Actually, sometimes we don't receive that, and we have to ask for it, but we're supposed to get it. And then we triage the submitted records and send them out to specialists in the area that they cover letter and their records indicate. They get back to us and make a decision about whether to accept or decline the patient and then tell the patients and the physicians. And then for the accepted patients, they come back to us for about a week admission, and we have a delay time now for admissions probably about two to three months for both pediatrics and adults. So this got a lot of press and actually Dr. Zerhouni was part of the announcement almost a year and a half ago now. And you can just sort of read all the people who are interested in this. This struck a chord with people. I think it's because many of them had trouble reaching, let's say, a team that would look at everything comprehensively and sort of universally. Instead, they'd have to go to one specialist, a specialist, and then another specialist, et cetera. So there was a significant amount of press. That's fine. So this is what happened. Basically, we're inundated and couldn't really handle it. And in fact, another way of looking at it is sort of loosey without the candy. So out of desperation, we sought more support and actually received support from the leadership of the NIH and from individual institutes and especially from individual investigators, many of you of whom are in the audience. The number of inquiries we've had since May of 2008 is really 2,300. The number of medical records is clearly over 900. I don't even actually know. We do have a database, however. Most of the patients we've been able to reject and many of them are eminently rejectable. Any of us would reject. Some of them are a little more questionable and I'm sure that occasionally we make some mistakes. But we have accepted about 190 individuals on many on my service and many on other services throughout the NIH to existing protocols. We have about 150 charts that are currently active and under evaluation. And 13 of the patients that we have either seen or were about to see have died before they got here or shortly after they got here. Which really speaks to the severity and criticality of the patients that apply to this as well as the number of patients who don't have that criticality. Most of the cases are actually neurological cases and many of the cases are pediatric cases that are very complicated. We now have expanded our personnel hired by the UDP to these numbers here or so. So we have a really reasonable contingent of individuals. And these are the personnel who are currently with us as paid personnel acquiring more sort of as we speak just working on a couple of other contracts. And the consultants here again a significant list of individuals from all the disciplines of the NIH. We have planning meetings in which we triage some of these charts and update the database and often we have to ask for specific further information in the form of slides or images and we get it. People really do not resist this. They get free medical care here. Of course there may be some other reasons too. And the pediatrics group now is headed by Dr. Cynthia Tift who's in the second row here. She just came on board as the deputy clinical director in NHGRI and she's conducting the pediatric portion of this now. Then we have open meetings once a month which is basically to sort of show off many of the interesting cases that we have with images and slides and a lot of contributing individuals here many of whom spend a considerable amount of time preparing for these meetings and then I sort of conduct the meeting and we learn about new cases that are of interest.  The genetic analysis in addition to using targeted diagnostics that are clear certified and molecular and are send out tests that we pay for, besides that we do some unbiased screening with SNP analysis. And these SNPs are done by Dr. Tom Markello through the NHGRI genomics core which we have access to and there's some significant software that's involved that was really developed in part by Tom and in part was able to be purchased. We're able to determine two things. One is copy number variance. In other words, supposed to have two copies. Do you have only one? Do you have none? In other words, are there deletions or do you have a duplication and have three copies? And runs of homozygosity where heterozygosity is no longer exists in this individual patient. And that can speak towards autosomal recessive disease or genes in the region of that's an inappropriate homozygosity that would be candidates. So the way that this works is a single nucleotide polymorphism is an area within the genome that has a natural variation in many of us. And it isn't a 1% to 99% ratio. It's really a 30, 70, 60, 40, 50, 50 or so. So these are common variants and they're defined by a single nucleotide but surrounded by other bases so that one can determine if the person has, for example, the A or the T in the first case or the C or the G in the second case. And so these SNPs are selected by Illumina in this case across the board and they're selected approximately every 3,000 bases so that one can determine to basically use these as signals or as markers for the absence of a region of sequence. And that absence can be on one allele or on two alleles or it can be a duplication and we can determine that and I'll sort of show you how in this. And so if you have, for example, 10 SNPs in a row that are missing, you know you've got roughly 30 kilobases missing and it may be a portion of a gene that's missing. Things of that sort are what we can do. And it turns out by convention that the less frequent allele is called the B allele and so everybody of us who is diploid is A, A, B, B or A, B. And this is a picture of the distribution of some of these individuals so that would be B, B, A, A and A and B and these are essentially intensity plots of the signal that comes out of a SNP analysis through the genomics core. So here, for example, is a listing of a number of SNPs with their R ratios and an R ratio is the ratio of the A to B, or actually B to A and if the ratio is one, in other words your heterozygous, you're logged to the base two of R is going to be zero. So for example, this means that the person is heterozygous because that reads 0.0084 which is close enough to zero. So the way that one uses this is to determine the intensity and if you have an intensity that's logs below the 0 to 1 or negative 1 to positive 1 range, namely here, if the intensity is that low it means it's deleted and then you can line this up with a human genome database to determine what genes are in that region, what genes could be deleted and what genes to be looked at for the causative gene. And in this case, when you expand the previous slide where there were only a couple of SNPs visible, here you have really all of these SNPs that have very low intensity, indicating a deletion. That deletion is 32 SNPs, 60 kilobases involved and in fact it corresponds to the particular deletion that I study which is cystinosis, a very common 57,257 base pair deletion which accounts for half of the North American and European individuals who have cystinosis. So this is sort of proof of principle that we can pick these things out. The other issue is you can measure heterozygosity versus homozygosity. And this illustrates that. So this now is the B allele frequency plotted on the ordinate and over here are the AAs. Their B allele frequency is zero. Here's the BBs. Their B allele frequency is one and the B allele frequency is 0.5 for heterozygos. So you can see that these are homozygos, these are homozygos SNPs and these are heterozygos SNPs. And this is a centromere for which there are no SNPs. So if you were to expand this on the next slide, you're only going to see the middle line. Only you're going to see the middle line for all sorts of different chromosomes. And here, for example, is a loss of heterozygosity or an absence of heterozygosity. So if you thought that this was an autosomal recessive disorder, you could look in this region, see what genes are there and they could be candidates. Now in general, this type of analysis will give you more candidates than you can possibly use so that really this is a first step towards pursuing a genetic diagnosis. So here's another area that you may have seen. And here's an individual whom we saw very early in the course of this program who gave no history of consanguinity, but if you look at all these spots, does have consanguinity all over the place and has approximately a three to four percent of all this person's genome is homozygous, which could correspond to roughly a second cousin relationship among the parents. Because remember, people who are first cousins share one-eighth of their genes. First cousins once removed one-sixteenth and second cousins one-thirty-second, which would be about three percent or so. So one can discover this type of issue. So let me tell you now about some of the cases that we've seen here. And remember, what I'm going to show you now is really a distillate of a huge number of charts that people have gone through and discarded with cause the majority of them. And so perhaps every decent case that we've seen here represents fifty to a hundred cases that have been looked through and called. We don't know what's going on with this next group of patients. And in fact, we haven't even seen yet. But she's fascinating in a way, because this is a before and this is the way she is now. And she feels that the room is so hot. I'm sorry. I think I can do this like this. The room feels so hot, but only on her face, not on the rest of her body. So she keeps the temperature in the room at fifty-eight degrees and has a fan blowing on her face. And her face is painful. And then nobody knows exactly why she has this autonomic symptomatology, but only in a segmental area. We haven't seen this patient yet. We have seen these kids, and they have short stature, dysarthria, bowel, bladder dysfunction, some dysmorphisms. And again, we've seen these individuals, but we don't know what they have. And so we're interested in having bone experts look into this. Here's a little girl who has cranioectodermal dysplasia.  In fact, she has a sister, and her sister is under psychiatric care, because her sister doesn't understand why people make fun of her sister. Her problem is that she has no roots to her teeth. Her sweat glands are missing. So she has many signs of actodermal dysplasia, but this doesn't really fit any particular of the 150 different types. And in sort of summary here, her main problem is that she has thickening of the skull, and this bony overgrowth is impinging on the optic nerve canal so that she has some papillodema as well. And that may need to be released at some point. Again, we don't know what's going on. Nor do we know what's happening with this girl with microcephaly and seizures and developmental delay. And believe me, there are many, many of these individual cases. Or this five-year-old girl who has liver disease and pancreatitis, and also some neurological delays. But the interesting thing from a metabolic standpoint is that within her liver, she has areas of beginning fibrosis, she has some inflammatory cells here, and she has copper accumulation. But the copper accumulation in her liver is not associated with Wilson disease or any typical pattern of that copper distribution, which is always in zone one. Instead, she has it in zone three, which is the furthest away from the vasculature. And our pathologists have said they've never seen this and neither have other liver pathologists. So this is particularly a different type of copper accumulation. She also has a biliary canaliculus here, and you can see the lumen. This is apparently abnormal. In other words, this should be a virtual space, not a real space that you can see. And this reflects the fact that the columnar cells are swollen and are surrounding that lumen. Again, we don't know what we're doing in this case, nor do we know what we're doing with these individuals who have all these different disorders, including one who has a major accomplishment and probably could increase that number. Now I want to tell you about some interesting cases that we actually have a lead on and that some people are working on. And here's a 21-year-old woman who has lung nodules, which you can see here. You know, these things do not belong there. And she has acides, and her ureter has been kinked, so she had hydronephrosis. All these things are thought to be related to her main defect, which again we don't know about. But on biopsy of the cheek overgrowth, she has this type of a pattern, which is both fibrous and inflammatory. And she has some plasma cells there, eosinophils, and she has some of the hematopoietic derived stem cell markers within that biopsy of her cheek and lung. In her liver it shows essentially the same thing, some fibrosis, but a lot of inflammatory material as well. And Dr. Kleiner has made the diagnosis of angiolymphoid hyperplasia with eosinophilia and a fibronflammatory disease, a descriptive diagnosis. And Dr. Axantinovich has discovered that there's increased IL-8 and IL-1R inner circulation. So these are clues towards the type of inflammatory reaction that might be occurring. And now we have a lot of other tissue by virtue of really a biopsy that Dr. Carter Van Weis did on her in a four-hour operation here at the NIH to collect material to try to find out what types of cytokines are being emitted and what type of therapeutic efforts we may make directed towards those inflammatory molecules. Here's a 46-year-old woman who has in her kidneys thrombotic microangiopathy, but she also has granulomas on her skin and interestingly increased circulating the vasculinothelial growth factor. This is her kidney biopsy, and you can see that there's thickening around the vascular wall and that the mesangium is increased within her glomerulus. She also has blunted podocytes, and this really is reminiscent of preeclampsia, which you know is due to the production by placenta of an inhibitor of VEGF so that there's no longer enough trophism by VEGF of the kidney cells, and therefore the patients get renal disease, hypertension, and the treatment is essentially removal of that antibody by delivery. In other words, get rid of the placenta, get rid of the antibody. So here's a woman who shows some findings of preeclampsia, but due to a different cause besides the placenta. In other words, it's probably a genetic defect either in the VEGF itself or possibly in a VEGF receptor. So that's currently under investigation along with a collaborator at Beth Israel. And this is the woman who was in the New York Times article who has some of the similar findings. She also has a thrombotic microangiopathy in her kidney. She also has problems with her venous lakes within her skull, and she lost her right eye because of retinal vascular problems, and you can see she has really systemic disease. She has actually died by stopping therapy because her therapy was so significant. She was losing a lot of blood through her gut and decided not to continue with the transfusions, and three days later she died. But she sent us her body, and we have performed an autopsy on it and have that tissue to study now. This is a 39-year-old man who had slowly progressive neurological problems, and you can see that there's some diffuse leukoencephalopathy which progressed at this time relatively slowly, but since then, I'll just show you a couple of areas where there's some abnormalities here, but since then you can see the extent of brain volume loss that this person has had over the last three years or so. And we brought him in on two occasions and probably bring him in again under Dr. Toro's service, and essentially excluded the diagnosis of leukoencephalopathy and made the diagnosis of progressive multiple, primary progressive multiple sclerosis based upon a number of oligoclonal bands, increased protein, increased IgG within the CSF. But Camillo also measured the BV antibody titers and found them to be elevated, and also the PCR was increased. So this wasn't just the presence of antibiotics, also the presence of the virus itself, and now Drs. Bilikova of NINDS and Jacobson of NINDS and Dr. Cohen, Jeffrey Cohen and Toro are investigating this EBV infection as a possible cause of primary progressive multiple sclerosis, which is essentially hypothesized within the literature, and this may be an index or a sentinel case that might be able to demonstrate that. Now, I just want to tell you about two success stories and then I'll sort of be finished. One is a 52-year-old woman who, without taking steroids and without essentially working out, well, she might have worked out a little bit, but she didn't work out like this, and it did not have any of the standard endocrinological abnormalities that might cause this. It had the development of increased musculature to an incredible extent, and this was becoming painful for her. She had strains in her muscles. Of course, she didn't like her appearance either, but in addition, she had real pain and it was becoming problematic. You can see on the CT scan here how big her perispinal muscles are. Now, some of us in the audience, perhaps half of us, might not mind this real much, but this is not a good thing to have, and these are her rib muscles, so she has incredible increase in the size of her muscles, and when we did CTs of her head, even the muscles that are essentially not used very often that we can't hypertrophy were hypertrophied. For example, the rectus muscles of her eye were huge, like three, four times as big as our neuroradiologists had ever seen. So, she has this for some reason. The EMG was myopathic, but a muscle biopsy was read as normal. We brought the patient in because this was fascinating. The referring physician from Duke said, in my 38 years, I've never seen... Okay. So, it turns out that we did a second biopsy. Even though the last biopsy was done only a year ago, and Dr. Kwan had it sent to AFIP and our pathologists here, and together made the diagnosis of amyloid myopathy. In other words, the amyloid was seen in the thickened walls of the vessels and stained on Congo red, and protein aggregates were there on EM. This led us to consider, I'm sorry, the possibility of amyloidosis, and in fact, one of the most common causes of that would be multiple myeloma. So, we looked for plasma cells in a bone marrow that we did here, as well, and found 10% plasma cells, which is sufficient to make the diagnosis and hadn't been seen before. And the follow-up is that Dr. Minoli referred her to the Mayo Clinic. Now, she was becoming short of breath and fatigued. She had involvement, a little bit of controversy, but it was considered she had involvement of her atria. And if she would get involvement of her ventricles, that's considered to be very bad and could easily lead to death within months. But at the Mayo Clinic, she underwent a stem cell transplant, had some post-transplant complications, but then recovered, is feeling very well now and is no longer having all of the muscle pain. And I'm told feels better day by day. We do expect a full recovery. And in the very, very rare cases in the literature, the muscle mass is said to go down to normal. So we feel very good that we've caught this. And I just would draw one sort of lesson from this, and that is that this is a woman who on two occasions requested to be seen at the Mayo Clinic and was turned down by the specialty clinics there. And frankly, probably would have been turned down by a specialty clinic here as well. So her access to medical care for this particular disorder was because a broad net was cast for people like her. And the irony of it is that when she finally was diagnosed, she was welcomed with open arms by Mayo Clinic. Oops. So then the last case is this Sib ship that we saw with calcification of the large vessels and also the joints. So can anybody tell if there's an abnormality here? So this is, of course, the bone and the kneecap. But this vessel here is without contrast. So this is a plane film showing the outline of her vessels. And here it is on a pelvic film. You can see all that. This hurts the patients because there's poor circulation and they can't, if they walk for a block, they have to stop and it hurts them a lot. And here you see it as well. Also all the way down to the foot. And then in the hands, there's calcification in the joints here, right here, here, here. It's all over. I didn't want to put arrows all over the place. So this is the pedigree. It turns out there are five children, they're adults. They're in their 50s and they have this all. And Dr. Bohm's lab with Cynthia St. Hilaire worked on this and got fibroblasts from a biopsy we did. And this shows the control and this shows the affected woman. And this is the acquisition of calcium over the course of three weeks. And in the control, there is none. After three weeks, this is all the stain for calcium micro crystals by an assay that they performed. And this is critically important to point out to us that the problem was not with circulating calcium or phosphate abnormalities, but really it was intrinsic to the cells. So that was the first step. At the same time, Dr. Markella was doing a SNP analysis and found a region of homozygosity here that was shared by all five affected individuals, but not by the parents. So this spoke to a recessive disorder and spoke to this region here, which could be affected. That region involved 22 megabases in which there are almost 8,000 SNPs. So this is a large region. And again, that's the issue here. This is a large region. There are 22 genes. None sort of were pointed out. None struck themselves to us as real helpful. But on the other hand, we had Dr. Saint-Hilaire and Dr. Bohm involved, so they suggested one. And they have now identified the gene in concert with us. And this is going to be, I think, important for learning things about the mechanism of calcification of vessels in general. And all this required a collection of specimens, all sorts of different specimens, which we continue to do. So it really is an important issue for us in our handling and distribution of specimens. So the good parts of this are that virtually every patient is pleased with the attention and the hope that we provide to them. And occasionally we solve a case. And you can see some of the cases could be new diseases. I think I've noticed that around the bedside, around the tables of discussion, this has brought specialists closer together over cases. It sort of reminds me of when I was a resident as opposed to a bench researcher. It bolsters our protocols, we think. And there may be new protocols that come from this. Not so good is the fact that our triage of necessity is a difficult process for us. And the patients who are rejected are not really happy. In fact, some of the patients who are rejected send me notes. I get a lot of notes.  And I think that that's something, maybe a topic of future discussion, maybe a whole conference could be held on that. But I would say that nobody has ever stood up and said you lie. So this is your chance. If everyone would like to stand up. Anybody? Okay. So we'll let that go. One of the other problems is that we have gotten congressional inquiries. And most of the congressional inquiries are from patients, from representatives or senators, whose constituents have not applied to the program. So they decided that they were going to go to their senator or representative first before actually applying. Of course, this makes the response very easy. But it's really not the appropriate thing to do. Okay. So we're a little bit late sometimes with getting back to patients. And part of that is because we're overwhelmed. And part of it is because our consultants don't get back to us in a timely fashion. And as I said, the patients we see are a distillate. And again, many of the patients really don't have the objective findings that correspond to their complaints. In the future, we need to expand our basic research investigations into some of these distilled cases. Because they're really good cases. And we worked hard on phenotyping them. We'd like to use this program as a model for how we use genetics in the future for investigating rare diseases. And we'd like to post the cases to this community here and ask you for your input. So if any of you have expertise in the disorders that may be related to the ones we have up here, please let us know. Because we're reasonably anxious to offload some of these cases. We'd like to consult international experts via the web and create UDP clinics throughout the United States, if possible. That is to say, if there's support on the behalf of the extramural people or the leadership here. So we found that in order to fulfill the mission of the UDP, we have to admit patients to our service and then consult other services. And that's one of the wonderful things about the NIH is that people are generous about their consultatory services. Again, many of the patients would not come here if they had to come to a particular specialty. And this is a program that really doesn't fit into the natural paradigm of professional advancement. In other words, a young investigator, I would not recommend getting involved as the major part of his or her pursuit in this program because it's so high risk. But the benefits can be enormous as well if you strike gold. Triage is difficult, failure is common, and patients are desperate. And I'll just give you the final example of how desperate patients are. Here's a 46-year-old man who began to have neurological disease, both cerebellar and cerebral. And this is what he writes. And this is the letter that his daughter sent to us over this. And I'm not going to read this and let you read this. I guess it's obvious that a program like ours can't be influenced by anything of this sort, but we will be seeing this patient in a week or so. So I think Hemingway said it best about the patients that we see and the difficulties in life. The world breaks everyone and afterwards some are stronger in the broken places. And I think that Throw also said the massive men live lives of quiet desperation. And this is a program that lets us see really the juxtaposition of science and sadness in the world and lets us as investigators see the human condition in the person of all the patients who apply and whom we see for a week here at the clinical center. Thank you for your attention. So I suppose I know, I think people should leave. But if anyone wants to ask any questions, I will stay here and answer them for the stragglers.


Trust your banking app your balance could be lying to you. Here's how some transactions like credit card payments Don't show up immediately and some pending transactions like restaurant tabs increase before they become final It's also easy to forget when certain recurring charges are scheduled and all of this could lead to Overdrafts return item fees or embarrassing card declines if your balance drops too low solution Go old school and keep some kind of physical checkbook or register or use an app where you can put in all your transactions manually


I'd like to thank the Nathan for inviting me to speak about my take on this subject. I was wondering how I would feel 20 minutes by talking about data management. And as I put this together, I realized that I could probably talk about two hours about it.  And unfortunately, yeah, you'll have to sit through that because there's no real point in me talking about data if you don't even know what the data is of. So please bear with me. The Pew is a modern Burmese exonym for people who once lived in what is now called Upper Burma in walled cities. We don't know what the Pew called themselves. They flourished during the first millennium CE and they assimilated with Burmese speakers who arrived around the 9th century CE. The last Pew text is from the late 13th century CE and their language has been largely a mystery for a very long time. At this point, we know very little about the Pew language. We know that it is a Trans-Himalayan aka Sonos Tibetan language, which is somehow related to the language that ultimately replaced it Burmese. But apart from that, we really don't know much. What remains of the Pew language are three kinds of data. First are Pew language epigraphic texts in an index script, this background image here. The second type of data are Tang Dynasty Chinese transcriptions of the Pew language in Chinese characters. There's the Chinese transcription of the ethnoman Pew in red. These are very extremely limited in number and difficult to interpret. The third remains of the Pew language are some borrowings in Burmese. If you attended last month's workshop, one of the speakers talked about potential Pew long words in Burmese. This is all that remains of the Pew. Pew has left no descendants. We just have two kinds of textual evidence in the Pew script in Chinese script. The third type are some words in Burmese that are thought to be of potential Pew origin. Most of my work involves the Pew language inscriptions, which are the largest body of evidence concerning Pew. These inscriptions are documented in several formats, one being photographs. These photographs vary considerably in quality. We have both photographs taken from the Colombe, from when Burma was a British colony, all the way up to the present. Many of these photographs have been taken by the photographer James Miles of Arqueobision. One might think that new photographs in color and high resolution so forth would be inherently superior, but often this is not true. Other photographs are better because items have been less damaged in the past. The photo here is of the most famous Pew inscription of all, the so-called Pew Rosetta Stone, which has four sides and four different languages, one of them being Pew and the other three being in other languages. Photographs also include rubbings of inscriptions. The previous photograph I showed you was of objects, but we also have photos of rubbings, including unpublished rubbings in the collection of Professor Janet Stardart of Cambridge. We also have so-called reflectance transformation imaging files, or RTI files, that were made by Oliver Riffens and shown here by James Miles of Arqueobision. These RTI files are made from multiple photographs of a inscription, and they are put together into a computer file that, when viewed with appropriate software, can simulate the experience of viewing the same inscription using different kinds of light. In this example here we see that these two vertical lines, which are Pew punctuation marks, you can see different aspects of them in different lighting. This is a single RTI file, but by manipulating software I can change the lighting and see things in different ways. We also, James Miles of Arqueobision has also made for us 3D photogrammetry models of smaller Pew objects. We are able to rotate these things enlarged and so on. These are the kinds of files that are generated from objects, photographs, rubbings, photographs of rubbings, and 3D models. Now, the problem is how do I catalog and keep track of all these things? When I first started working on Pew two and a half years ago with the mission to try to decipher the language, I only knew of a few inscriptions, so I didn't feel the need to number them. I came to Pew studies from Kitan studies. Kitan is an extinct central Asian language, also primarily preserved in the form of inscriptions. And Kitan studies, for whatever reason, no one has ever come up with any kind of cataloging system. So there are no universal numbers, there are no universal conventions, it's a complete mess. And I, unfortunately, inherited this chaotic mindset, which turned out to be a disaster because it turns out there were a lot more inscriptions than I had thought. Here is the so-called inscription house in Burma where there are multiple Pew inscriptions. As a starting point to resolve this mess of cataloging, Charles de Rozel in the early 20th century came up with initial inventory of Pew inscriptions. His first inventory had just five items. He eventually enlarged this to have 15. More and more inscriptions were found over the following 80 years, but the problem with Pew studies is that after the colonial period, Burma had gone through some rough political times and Pew studies basically were frozen in time. And so, fortunately, a few years ago, Arlo Griffiths and Julian K. Wheatley picked up where de Rozel left off, adding 155 inscriptions to his list of 15 for a total of 170. And Arlo and Julian have collected these inscriptions in an Excel file containing these various fields. Now, what I could go on and on about all these fields, but the field of interest to me is numbering the numberless items. Now, how are you going to, or how is one supposed to number these things? They, almost none of these inscriptions have dates, so we can't arrange them in any kind of chronological order for the most part. The few dates we have are terminus aquaul. They tell us a point where we know that the inscription must post date, but it doesn't tell us exactly when it was made. And a few dates are in a calendar we don't even understand. So, we can't use chronology to help us organize these inscriptions. Geography is not all that helpful either, as most of the inscriptions come from three sites. So, ultimately, we ended up using Durazal's original 15 in their arbitrary order. And the remaining 155 inscriptions were grouped into thematic groupings and numbered consecutively within each grouping. So, 16 through whatever is the pure inscriptions in stone, pure inscriptions in the polylanguage were another set, and so on. Unfortunately, new finds that fit into these earlier categories are just dumped at the end, and this is unfortunate, but unavoidable. And new finds are being found all the time. Here's an example that I found while I was visiting in Burma exactly a year ago. We went to an archaeology office and boom, we were told, hey, we just found this two days ago. Now, what I do with all of those photographs and whatever is I try to transliterate the text. So, this is taking the raw material, taking the raw materials, we're converting it already into photographs and so on. And this is the next stage where I take the text and try to convert them into letters. Now, generally speaking, pure is written in an index script. They are conventions of how to convert index scripts into roman script. And so, generally, we follow them. But one huge problem is that we don't know exactly how pure was pronounced. And this is a problem because it means we don't really know how meaningful this transliteration is. We're just, I'm just mindlessly copying letters without knowing exactly what they stood for. I'll get, and then I take these letters and I put them into XML files, one per description. These XML files are in the Epidoc standard and they contain all sorts of information, such as other people's readings in the past. As a phonologist, I then take these readings and chop them up into little pieces, like constants and vowels, and these are put into columns in Excel files. Now, earlier today, we've come up with, we've encountered the theme of version control and why is that important? Well, here's a personal example. As I said before, we don't really know much about how pure was pronounced. We're just mindlessly copying letters and converting it into roman script. So, there is this subscript dot in pure that is very, very common. And for a century, people had different arguments about what this dot stood for. When we first started transcribing pure, we just arbitrarily decided, okay, we'll just make this dot an apostrophe and we'll stick it after the last constant before a vowel. Later on, we changed our minds and decided to mark this as an M with a dot, since M dot is a convention in endology for writing superscript dots. We thought, oh, it'd be really clever to use M with a subscript dot to write a subscript dot. Now, here's where version control came in. This isn't just for 22nd century archaeologists. The problem was that I've mentioned my Excel file, I've mentioned XML. We also had RTF and text files. Migrating the data through all these different formats meant that when we change our minds about how to transliterate pure, it meant that we had to, of course, change all the other stuff in the other formats. And this is where version control became crucial because searching replace with pure is a nightmare as I tried to use regular expressions to do search and replace. But pure structure is so complicated that a simple formula doesn't quite work. Also, there were typos and such where the apostrophe was the wrong place to begin with. And so I did innumerable errors and had to convert things over and over and over again. And sometimes I would think, oh, I'm done. And then I would, I also use GitHub, by the way. So I'd upload things to GitHub and I'd discover, oh, God, it's all wrong. And so this is where version control comes in handy because you go back to your old version. You try to diagnose where your search and replace went wrong. You undo that. You do the search and replace again. You re-upload to GitHub. So that's the value of GitHub for me personally is this type of error management of discovering where I went wrong in the past of restoring the old data and so on. I've mentioned GitHub, the XML there, we then move to the publicly accessible site purpose of Pew Inscriptions. My attitude toward Pew Decisement is an open source kind of attitude. I like the idea of having the public being able to look at the same data I do and come to their own conclusions about it. This website contains the latest version of the XML for the Pew Inscriptions. It's synced with our GitHub. It contains images of the inscriptions and a bibliography of Pew Studies. We've already mentioned Zinodo previously. The XML, the photographs, the RTI files are publicly archived at Zinodo. The future steps with data include some that I forgot to mention here, so I will. I've been talking purely about Pew Script stuff. Future steps include, well, if we just start with the Pew Script, I'm working on an archive of images of Pew actuals. Actuals are our character combinations representing syllables. All this colored material here is a single actua for the word for PIN that I translated as Kedah. These acturas, I have taken screenshots of them and I am building an archive of them so I can try to break down Pew Script into its components and look at how different letters take different shapes and different environments and so on. All of this will eventually be publicly archived as well, but this is still in the compilation process. Using this analysis of Pew Script, I hope to come up with a proposal for encoding Pew and Unicode and at some very late stage, ultimately convert the Pew texts back from this transliteration stuff into the original Pew Script in Unicode. Lastly, other data that I plan to work with in the future are, for instance, the Chinese transcriptions of Pew, which have never been systematically analyzed. That too will all be publicly archived. So I am going to now end 12 minutes early and we'll see if we can have a record number of questions. Yes? Are all the inscriptions just about Kings, Battles and Donations or is there some more interesting material in the inscription? Oh, well, the state of Pew studies, as I said, well, considering that we hardly know how the language is even pronounced, right now we only know about 200 words. And so quite frankly, most of the inscriptions are incomprehensible at this point. I mean, what I do when I transcribe these things, I feel like some kind of mindless robot much of the time because I have no idea what these things are saying. One saving grace of Pew is that it is an index script, so we recognize the letters, but the effect is like for most people here would be familiar with Indo-European languages, the effect is that of looking at Hungarian or Finnish, where you recognize the letters, but the text is just completely alien looking. The language is very distantly related to Burmese, and I have studied Burmese, and frankly it really doesn't help a whole lot. So the point is that we just really don't know what most of these things are saying at all. Some are our funeral texts because we recognize things like die, we recognize dates, so we assume those are death dates, but we don't really know. And we assume that the king and the name on it is the name of the deceased, but this is all assumption really. I mean no one has really come up even with something as simple as a really good word-by-word analysis of these alleged funerary texts. We just recognize these words and people jump to conclusions. A lot of Pew studies is highly conjectural and this is not really emphasized because people like pretending they know what they don't. So anyway, bringing back to a more database theme, the fact that we just understand so little makes cataloging this stuff really, really difficult. I mean I gave just enumerating the inscriptions as an example, but just trying to figure out how we're going to convert this into letters. I mean you can base it on Indic conventions to some extent, but there are things like subscript dot and other oddities that have no Indic basis. And I've argued with my colleagues back and forth, what are we going to do about this? And then it's like, okay, well let's search and replace and try it this way. No, and then let's do version control and undo that. And back and forth and back and forth. And that's because so much of this is just so unsettled. I think what you may find of some interest in my talk is that I'm dealing with the problem of cataloging almost total terra incognita. That's a very different issue from what other people are working with, I think. I mean just trying to figure out what categories to put things in is a mess. I mean the fact that you asked about the content of inscriptions, I really can't use that as a method of cataloging them at all. I mean I don't know what these things are saying and that's why the categories for the enumeration are just so crude. Is it on stone or is it on metal? Yes. So you mentioned that the XML files as a zip file are all on Zododo. Yes. And the primary sources in terms of photographs and RTI files. RTI files are big so I presume that you can't fit that all in one Zododo record. So how are you keeping track of the relationship between the different Zododo submissions? Each Zododo submission is cataloged by the Pew inscription number. And so I looked up things in Zododo by those numbers. And under each number there's a huge file with the RTI and the photos. Frankly what I don't like about Zododo is that I can't just grab a single file out of these huge collections. Oh that has to do with how they're uploaded I think. Yes. Because they were uploaded as zip files you have to download as zip files. Right right take them apart. But if I had uploaded them as individual files then it would have been easier to use. Yeah but on the other hand then we would have like hundreds of files per inscription and that would be a different sort of problem. Yeah because RTI files require many many photographs to create a single RTI file that can be viewed with simulations of different kinds of lighting. Yes. You've made your data available in the Epidoc XML format. I was wondering if you comment on how much work that was and what the benefits of that? The benefits of Epidoc for me are that it builds a bridge between Pew studies and other kinds of epigraphy I think. I mean one weird thing about Pew studies is that it is it has been basically an island totally cut off from everything else. I mean even within Santa Tibetan linguistics it is pretty much cut off from everything else. When I when I studied the Epidoc standard Daniel and I went to of all places Romania to take classes in Epidoc we studied along with classicists using Epidoc for Latin and Greek. And the strength of Epidoc I think is that it's a shared format that is usable for any kind of epigraphy and so Greek and Latin epigraphy experts have encountered many problems already and have found solutions for them. Pew is still an infant field barely explored and so it is nice to have this body of expertise available that can be recycled for our own purposes without us trying to have to try to have to reinvent the wheel and I find that that valuable. I think Pew is just so unstable and so mysterious that any kind of help I can get is very much appreciated and using an existing standard like Epidoc that has been around for a long time helps toward that end.


He is speaking here at the Edmund Burke Foundation national conservatism and of course He's going to talk about LGBTQ plus people and he's essentially going to throw his entire community Under the bus not the first time he's done this won't be the last time but either way what he says here is just genuinely disturbing and it's like Cutting off your nose despite your face like he's only hurting his self by associating with these types of people and Trying to you know pay pay lip service to them. Let's watch though And I know plenty of gay people that are horrified at what is coming out of the gay community now.  So do you think he's gonna cite any specific examples? Probably not because it's Dave Rupin But horrified what is the gay community doing like I don't I don't know What are they doing trying to survive trying to exist this year?   I think actually for gay marriage I lived in West Hollywood in in LA. It's it's sort of the gayest place on earth. I mean the crosswalks are rainbow It's too much frankly I Cannot handle the fakeness of these motherfuckers Why?  It sounds like Trump, but that's not what I mean Carries his little dog and and has nothing to live for other than that and maybe being on the hunt still because he couldn't engage Because 50 years ago the world was very hostile to him and Hang on a second first of all To talk about someone else with a spray tan This you are you not plastering orange on your face as well, but like You're literally making an assumption About somebody based on just like seeing them on the streets Oh, well this like one old gay dude that I saw who has a fake tan and his dog. He has nothing to live for What? You're making all of these assumptions.  We could say the same thing about you Dave Rubin Why are you better than him and even if that were the case?     Where are you getting this?  They've demonstrated that time and again. So what are you even talking about here?  I think that the dog's can probably expand a lot better I mean that the T thing is completely just dysregulated the entire conversation here But the T thing meaning trans people they've dysregulated the entire conversation He knows being trans is not a new phenomenon Even if gay rights specifically have advanced further than trans rights These have always been one movement Trans rights and gay rights.  I just like what's the maximal dream scenario here bud? In order to give the Christian majority the possibility of running a Christian society Oh so when we're talking about dream scenarios you know not for gay people But giving the Christian majority the authority to run a theocratic society That's when you know you have to make some compromises with us In areas right that's Not only do I accept that I would I will be very clear I would strongly prefer that public schools teach the Old Testament and the New Testament Rather than drag Queen's story hour so Wow so Dave Rubin just said he'd prefer what this religious theocrat said A version of Christian society And Dave I promise you you don't want that because let me tell you what the Bible says about queer people And you know you just said you'd prefer that the Old Testament be taught in schools as opposed to drag Queen's story hour But what does the Bible tell us about homosexuality?  You might want to be careful what you wish for because in a theocratic society Not only would your children be taken away from you But if these dipshits had their way they would stone you for being gay So he's this man is literally with the straight face saying I welcome this theocratic society Because I think that conservatives would I guess not stone me I mean look if it's not apparent to you by now that he's saying all of this specifically for a check I mean it never will be because he doesn't believe this Dave Rubin doesn't believe this Dave Rubin is a grifter and he's saying what he needs to say To get the conservative seals to a plot so we can keep cashing that check But it's so gross and craven I mean look he bought a mansion he probably has millions of dollars When is enough enough I mean is this the world that you want to raise two children in Where they think that their parents are perverts and disgusting and less than Is this really the world that you want? Like this is so gross Dave Rubin is one of the most disgusting morally bankrupt people on the internet And this is why he's like the number one grifter in everyone's minds Because he will say anything and it's just so gross As long as it gets clicks and money he'll say it


Welcome and aloha. My name is Mark Shklav. I am the host of think tech Hawaii's law across the sea program Today we're going across the sea from Chicago and South Bend to Tokyo and Seoul and ultimately to Hawaii and talk with Hawaii attorney Stephen Dyer about his journeys in Japanese language and culture the practice of law and service in the u.s. Army and how all these roads Connected and ultimately converged in his personal and professional lives Welcome Steve. How are you? Thank you, Mark. It's good to be here. Okay, we're we're we're looking at a beautiful photo of you That appears on your website page of your law firm. What law firm is that by the way? It's Okay, all right now but before we get into your Law practice and talk about that. Tell me a little bit about your background your personal background where you're from Where you grew up and then I know you went to Notre Dame undergrad and John Marshall law school, but trying to just give me a little background on yourself That's correct. Mark. I grew up in Just outside Chicago a town called Juliette, Illinois I did my time figuratively That's a film that's known for a prison. Yes. Yeah, okay couple of them correct You know, I went to july at catholic high school all boys and my dad was An army in world war two. He was a an infantry company commander with a 36th infantry division that went from All the way up Italy into southern France And I was kind of into high school. I didn't really worry about college and one day he comes up And there you go. So what are you going to do next year? I go, I don't know. I haven't thought about it He goes are you going to go to college? This is my senior year in high school And I go, yeah, I guess so and he goes, well, how are you going to pay for it? And I look at him and he goes, this is not going to be me. So he better start applying for scholarships And he had Brandon filled out a scholarship application for an army ROTC scholarship And he goes, you just have to write an essay and sign it and I'll send it in for you. I go What's ROTC? He explained it to me And I said, okay, I get it. He's the next officer. So Okay, I'll sign it and so bottom line is I got the scholarship and It was funny. I had applied to Notre Dame and brought up for a new view and The admissions counselor's like, oh, you know, we haven't reviewed your your application yet, but Have you applied to other schools? I go, okay, I get it. Um, and then the next week I was informed I got the scholarship and This army colonel had called me and I told him the story of this admissions counselor. He goes, oh, really? I'll call you right back And he calls in 15 minutes. He goes, guess what? You've been accepted So I thought, okay, um Then at Notre Dame freshman year all the freshmen have to take the same core courses five courses It's how they weed you out And one of the courses is a modern language So I had taken Latin and french in high school of three years each and I figured I'll take french to I'll get my C and kind of cruise and that'll be it Sure enough after the first semester I got my C, but then Second semester the first week. I didn't prepare And the french prof took me Friday afternoon after class. He goes, let me show you You were not prepared today. I go, no, but I'll do better on Monday. He goes, no, no, no If you come Monday, I will flunk you You better go to the dean because I know you need a language or else you're out I thought that's pretty harsh, but I went to the dean Dean goes out Oh, I took the liberty of calling the french the Spanish prof the german prof the russian prof Nobody wants you. Um, you'd have to make up a whole semester in a week and anyway, um Oh, hold on the phone's ringing And he hangs up and he goes that was the japanese prof You need three students to have a class at Notre Dame or else they cancel the class and He just lost his third student. So you even go over there and be his third student You better pass dire or else you're gone So fear is a great motivator mark. I uh, I studied very hard so I think that was actually a guardian angel in disguise taking care of me because He recommended the prof did that. He says, yeah, you you've normally caught up But I want you to go study in in tokyo your sophomore year and I did and then I wound up the majoring in japanese along with economics and At Notre Dame You had a kind of a dual major is that it at Notre Dame? At a double major, correct. And Notre Dame has a program that are somehow you were got to japan as an undergraduate Is that correct? Correct at sophia university, which I believe you went to yeah mark Yeah, I went to as an undergraduate also for a year. Yeah But you you were there for two years. Is that correct? No, I was at sophia for just one a year abroad actually in nine months. Okay But then during last school Okay, so I was you know, I owe the army four years since they paid for four years of undergrad because you've got a scholarship to attend Notre Dame through the the rotsi program Correct. Okay. And then so I was able to get I'm sorry and then and then because of this this fluke in this language is what got you hooked on japan I guess where you had to take the language. Yeah Okay, and so So I was able to get a Well, I was able to get an educational delay. They call it a deferment of the army commitment for three years for law school, but then I received a rotary you've heard of, you know, rotary clubs a rotary international Ambassador fellowship to go study at a japanese law school Along with a preparatory 15 month period of only intensive japanese to get to a law school level Um, and then they sent me to chuo university law school, which is the largest law school in japan. That was not easy but um So I did actually a five-year took me five years to get through law school, but um I learned japanese, so it worked out great and then because of the uh tours in japan as an undergraduate in Notre Dame and then ultimately In in john marshall law school Because of that scholarship now. I didn't know they had scholarships or are um programs In law school like that that's that's pretty cool. That's pretty nice But ultimately that's how you gain your knowledge of japan language and culture Uh this boy from uh, illinois Yeah And Yeah, exactly go figure. Yeah kind of so so and and uh, as I understand it, uh, all of these Things kind of played into an interest that you had and and you you got hooked not only on on, uh Japan but on the law and military and I mean what what in your background, uh Directed you to that area to those areas to those roads So that was No, I'm sorry. That's very perceptive of you mark. Exactly. Um, you know, I was adopted at birth And I couldn't have been blessed with two finer parents. They were magnificent um, I love them greatly um, but The army when I finished law school the army, of course said, where do you want to go? I go, well, how many You know, I was going to be a jag officer in the in the legal system And I go, how many Jags you have are fluent in Japanese? I go, uh, good point And so the next week I got my orders for Korea and kind of typical army and uh But that worked out because if you know Japanese I was able to learn Korean pretty well. So I didn't get around in Korean too um And then after Korea they sent me here to Hawaii And I became triplers Uh, medical claims judge advocates. So I did all their medical malpractice defense and One day during that time I showed up with chest pains one morning and You know, I was kind of concerned and you know, you get to know the chiefs of all the services So I called my friend the chief of cardiology who said, you know, get up here right now and He asked me what my family history was for heart disease and I go, uh, I don't know I'm an adoptee so he goes you better track them down So I did It took five years and in the meantime, I got out of the army and started private practice here But The the adoption folks Catholic Charities called me and says well, we have good news and bad news for you The bad news is your mother passed away your birth mother um But she had a sister and the sister lives in Honolulu Within an hour that sister was in my conference room and we're you know, I'm looking at photos and finding out things They in turn looked me up with my birth father and uh The weird thing was I found out my my birth father told me yeah, you're from a long line We have a genealogy goes back to 1254 in England You're from a long line of lawyers and military officers. Wow and we're all linguists amazing. Oh my gosh It kind of all made sense it's like uh, uh, some uh invisible hand is moving the uh pieces on the chess board so that Yeah, all these things come up because I mean But for the army you you wouldn't uh be in Hawaii Uh, but for working at tripler through the army You wouldn't have found your parents basically because you know you went to the doctor and he gave you that advice And then and then you find out this long long history And and and you're you have a relative right in Honolulu. I mean, it's kind of how do these things happen Well, and not only that but the weird thing is the my auntie who lives in Honolulu here It tells me that her father so my birth grandfather is a 1923 Notre Dame grad So maybe that was my guardian angel when I got kicked out of french, who knows Okay, so uh in in the army when you were in korea, what kind of cases were you handling? Uh, they put me in what's called the trial defense service and I was there 27 months. I did 27 jury trials court marshals So it's defending soldiers who've been accused of crimes. So all criminal defense and all trial practice basically Correct. Yeah, very good experience. Yeah, and that kind of set you up I suppose for what you're doing now. Is that what your practice is now? At your law firm sort of I'm still a trial lawyer. I'd like to think so anyway. I'm a litigator But I don't do criminal anymore. I do all civil so lawsuits. I defend mostly Some plaintiffs work to mostly actually for Japanese plaintiffs who don't understand English well enough. I'll represent them As well as military folks. Those are kind of, you know, the soft spots in my heart but Mostly defense. Yes Okay, so you uh Study Japanese You learned about the culture because you spent a number of years as an undergraduate law student there and You had a military background Also in in Asia and then ultimately you came back here to Hawaii and Hawaii's your home now. Is that is that is that where you're you're you're staying and working and living Absolutely I fell in love with Hawaii when I came here in 1988. So I've been here. What whatever long that is Yeah, um, and I didn't hurt Go ahead and look I want to take a minute break right now And then I want to talk about The convergence of all those roads of military Law and japan when we come back an interesting Incident so I'd like to talk about that. We'll take a break and be right back Aloha, I'm Daelyn Yanagita one of our hosts of our business in Hawaii talk show on the think tech Hawaii The theme of business in Hawaii is to share with you stories of local businesses by local people And our guests share with us their journey to building a successful business right here at home We are streamed live on think tech weekly at 2 p.m. On thursdays. Thank you so much for watching our show I am Daelyn Yanagita and we'll look forward to seeing you then Aloha, I'm lillian cumick host of lillian's vegan world the show where we talk about veganism and the plant-based diet Located in Honolulu, Hawaii. I am a vegan chef and cooking instructor and I have lots of Information to share with you about how awesome this plant-based diet is so do tune in every second thursday from 1 p.m. Aloha Aloha, we are back I am mark schlaufe interviewing steven dire steven is a hawaii lawyer And he said several interesting roads that he's walked down From studying Japanese language and culture at Notre Dame and john marshal law school or through programs offered by those schools becoming a military officer jag core and Ultimately coming to hawaii and and steven Uh, how do you explain all these roads converged? And on february 9th 2001 something happened you got a phone call. What was that about? Yeah, you know everybody Wants to be the right guy in the right place at the right time. I think and Everybody will have that moment and and I think I was according to that moment on that date that evening, um, I went home and I got a phone call from the staff judge advocates in other words the chief lawyer for Pacific Command, which is the four-star command up at camp smith um For those who don't know camp smith the four-star at camp smith is it's a joint command and the four star is in charge of all u.s. Military assets From california to india. So it's essentially two-thirds of the planet's surface It's the most powerful and largest military command in the history of the planet Um, I was fortunate enough when I got off active duty um The jag office up there needed a reservist um So I was a reservist but this is a command for cheese 17 years. Uh, it was a very fulfilling experience being a reservist up there being able to Speak japanese korean and being able to be be sent all over asian kind of have a knowledge of of asia although funny Paycom sent me just about everywhere, but japan and korea mostly thailand and vietnam and australia new zealand Malaysia, but it worked out fine, but on that evening I got a phone call. This is probably the one big occasion when I was able to utilize my japanese and my experience in japan There had been a horrible accident. Um I'm sure listeners If you're older than 25 effort of the ahime madhu incident where a japanese Kind of a fishing trailer, but an educational vessel That the prefecture of ahime, which is in the shikoku island of japan commissioned to teach high school kids To be fishermen. So kind of a tech uh center Vessel And they did a dock in hawaii for a few days and it was leaving here. It was about six seven miles offshore One of our navy subs the greenville uh did A maneuver called an emergency blow Where they pretty much go straight up and kind of breach, you know, like a whale would breach out of water And uh, they didn't check to see if anything was up there They figured middle of the ocean what's going to be there and They struck The the aim a moderate the the fishing vessel and they cut it in half and It began to sink immediately And nine of the crew and students Were lost at sea were killed. So you were very sad very tragic So you were brought in to help I guess with the Diplomacy and because they knew of your background and what did you do? Correct, so The staff to javica called and said hey steve, can you help us out? You know, we know you you speak japanese and You know, you have a history living in japan Um Can you please help out push through a lawyer that won't hurt? Um So I was the first Representative of a pacific commander Anybody other than the coast guard who fished these guys out of the water that night Um to visit them and uh I introduced myself to the captain and You know his crew and uh To find out what happened and to find out what their needs were And tried to help them, you know, accomplish their their needs. First of all, they were at Sand island in the coast guard facility there. In fact, they had to throw them in the bridge because they had no other room And they lost all their clothes and so They gave them prisoner jumpsuits. They're all wearing these orange jumpsuits for the brig I kind of felt sorry for them and frankly they were just in shock still I think and uh I was able to report back to pacific command, you know, their version of events and uh Pacific commander still interviewing On their side to to find out what happened with the with the submarine folks, but Uh, I was able to convince them to give them what's called salatia international law That's just money so that they can, you know, get phone cars to call home to tell their loved ones. They're okay and To go out and buy some clothes that they could get some clothes with because they'd lost everything so They told me hey, just give the The captain a check and I go you can't do that. You got to do it the Japanese way You got to you know, have some sensitivity here and I was able to Convince the finance officer to contact the banker to get you know, crisp Brand new 100 dollar bills Uh and put them in envelopes for each of the survivors. There were 35 of them And have each of the envelopes inscribed in kanji with their name So, you know to make them feel more comfortable frankly With the the cultural way to progress and that's based on your background in in japan and what you learned there It was it's all about doing the right thing and you know, you just have to take care of these folks The right thing is good. That's a japanese Cultural concept too, I think Yeah, and then so what else what else happened? that that was a Friday night and then Saturday I got the cash and by Saturday evening 24 hours later the facts have been sorted out and It was clear that was our fault and in the meantime, you know, the tv network cnn was rife with reports of you know the japan u.s relationship going down the tubes basically and so I asked permission to apologize to the captain and crew When I handed over the solacea cash And I was granted that permission How did you know to do that? I mean that's an interesting cultural idea also Well, I was fortunate that I I had called the interpreter who I'd been using for Many years To help out. She's japanese. Her name is jesco kawakami. She was a huge help um But also I had gotten a black belt in the martial art of eidol Eidol is the The samurai sword and I think half the time when you learn the idol you're in the seiza position and you learn The ritual actions of you know bowing and apologizing it's all about being humble and um So I utilized that training when I conveyed the checks or that checks the cash And you know apologized to each one It really came in handy. I think it made a a big difference in trying to make Lemonade out of this lemon Yeah, and I believe that, you know, you've been complimented about that also by Uh, superiors is that correct about the way you handled it? You know, I hope I just did the right thing. I was just doing my job. Um They did give me a a medal No big deal. You know, I was just doing my job Like I said being the right guy in the right place at the right time. I think okay. Well, it looks like actually You've been in the right place at the right time maybe without knowing it All your life because uh all these things seem to work out, uh and point you down the road in In a direction where all of these concepts converged Japan Culture and language military and law Put you in the right place at the right time Yeah, I've been fortunate. There's a guardian angel somewhere out there. What what have you I mean What what can you tell us? What have you learned from all this if we have a About three minutes left in our program. What what have you learned? What have you learned from all this? Yeah, you know, I think I've stated it, but it's just doing the right thing You know as attorneys mark you're an attorney so you know we're problem solvers and You have to approach each problem You're giving a set of facts and you got to make the best you can out of that set of facts under whatever law that applies and so Hopefully I've learned well Approach problems from a legal point of view and remember at the same time. It's not our legal application You have to incorporate the human side of things as well and do the right thing In that regard has you know the culture of japan helped but been Benefit to miss your No question. No question You know learning another language and a culture opens your mind So you become more open to other ways to approach things and and doing things the right way You know doing the right thing Transcends any language or any culture so That's the beauty of doing the right thing You're fluent in any language when you do that now if I was A young person like you were when your father asked you what are you going to do Next year, what would you tell him about? your experience Tell me if I was the young young guy that you were talking to Me I was lucky You might not get as lucky as I was Just work hard Do whatever you're doing. I mean that's a cliche, but That's what it comes out. I mean you'd you'd recommend those roads japan study and Military and law All of those ideas seem to work out for you Is that you tell a young person to think about them and maybe Investigate the same type of scholarships that you had You know, is that something that you'd recommend?  So Figure out what you want to do and Be persistent. Well, don't give up. Yeah, that sounds like good advice. And also you were You you were kind of pointed in those directions, too. There was some outside influences. I think Somehow And maybe pay attention to them, I guess is that is that something Folks should do pay young people should pay attention to these things that come out of the blue, I suppose listening Yeah, is uh, it is quite a skill that you have to develop. Yes. Well, Steve Thank you very much for being my guest today I I like talking about all of these interesting roads and I have some of them in common and So it's it's very fascinating to me. And thank you very much. Aloha


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