 Good morning and welcome to the Undiagnosed Diseases Program press conference hosted by the National Institutes of Health. This press conference will last for 60 minutes. There will be five primary speakers who will provide brief remarks and then members of the media will be able to ask questions. To ask a question, you can press star and one on your touch-tone phone to enter the queue. You may remove yourself from the queue at any time by simply pressing the pound key. This call will be recorded, transcribed and available on the websites of the NIH Office of Rare Diseases at rarediseases.info.nih.gov forward slash undiagnosed. And the National Human Genome Research Institute at www.genome.gov. Now it's my pleasure to turn the program over to your moderator, Larry Thompson, Chief of Communications at the National Human Genome Research Institute. Let's continue. Good morning, everybody. This is Larry Thompson. On behalf of the National Institutes of Health, Office of the Director, Office of Rare Diseases, the Clinical Center, and the National Human Genome Research Institute, I am pleased to welcome you all to all you news reporters who have joined us for this tele-breathing. Additional material related to this announcement will be available on the websites of the Office of Rare Diseases and the National Human Genome Research Institute. Our expert panel in the speaking order this morning will be the NIH Director, Dr. Elias Serhouni, Dr. William Gall, the Clinical Director of the National Human Genome Research Institute, who will be managing this project, this program. Dr. Steven Groft, who is the Director of the Office of Rare Diseases, and Dr. John Gallan, who is the Director of the NIH Clinical Center, which is the hospital here at NIH. And we have a speaker, a special speaker from the patient community, Amanda Young, who has been had a difficult disease diagnosed here at the Clinical Center. We'll be able to talk a little bit about what that experience is about. But let me start by introducing Dr. Serhouni, who will give us some opening remarks. Dr. Serhouni. Thanks, Larry. I'm Elias Serhouni, the Director of the National Institutes of Health based here in Bethesda, Maryland. I'm really pleased to help launch this great initiative of the Tribunal Program of the NIH. And this will, in my view, could be very transformative, because in my career as a physician, one of the observations I made over time is that physicians deal with about 6,600 conditions, and 6,000 of these conditions are quite rare. And what I experienced in my life as a radiologist in practice is that often we were sent patients whose disease was undiagnosed. And so this problem is trying to address head on the issue of undiagnosed diseases. Why is that? First of all, many times what you will see is patients who've had a disease that was undiagnosed for years, and yet the disease was known but rare. And therefore the skill set, if you will, that you would encounter in the community would not be sufficient for a rapid diagnosis to be made. So you had a lot of anxiety, a lot of pain and suffering and expenses that often were not necessary because the disease was already known. So accessing a team of experts, as the experts we have here at the NIH, which is a unique combination. There is no such combination around the world. We have over 1,600 physicians all specialized in very, very, in great depth in the diseases that are of concern to them. So we thought that this would be a great advantage. But then as science has evolved over the past few years, what has become quite obvious is that even common diseases have many subtypes. And what we are finding, for example, through the genomic research that we've done over the past few years, is that even a common disease like diabetes, which is known today to have type 1 and type 2, type 1 for young children, type 2, may actually have many, many, many different subtypes. When I became an NIH director there was only one gene that was known to be involved in type 2 diabetes. Today there are over 16 genes that we still do not understand, for example, in diabetic patients why some respond well to treatment and some don't. So over time I think what is emerging is this concept of personalized medicine where rare subtypes of a common disease also present a diagnostic challenge. The third area where we are interested is the emergence of new diseases. More and more we are seeing, in fact, new manifestations of diseases, new causes for diseases, and diseases that are completely not understood at this point. So the idea of this program is to try to combine our many, many, many, many years of knowledge here at the NIH and offer for the first time our combined multidisciplinary knowledge to launch this undiagnosed disease program here at the NIH to assist patients around the country and their doctors. Because we believe that there is not only a service to be rendered, but also knowledge to be gained. And ultimately I think what we are facing right now is a complete change in the way medicine is going to be practiced. We are going to see patients earlier and earlier in the natural history of their disease which makes it even more difficult to diagnose. Children, for example, sometimes it takes a year or two to find out what exactly ales a young child. That we cannot afford anymore because by the time the time has passed damage has been done. We need to preempt disease and this is where I think we will learn how to do that and this new unit of the NIH, combining all the institutes skill set will be critical to this effort. It will really usher the new era of personalized medicine and will help us understand what I think is happening. And that is that we are now reclassifying the diseases as we know them as well as understanding the rare diseases that many out there do not yet understand because of the complexity of the science that is required to understand them. No team, very few team in the world can put those skills together and this is really what we are announcing today. This is a transforming initiative. This is something that we hope will advance science but also reinforce the role of the NIH over the years which has always been not just the National Institute of Health but the National Institute of Hope for many patients with diseases undiagnosed. So with that I will let my colleagues from these institutes and centers let you tell you more about this exciting new program and I will turn it over I think to Bill Gall at this point. Thank you very much Dr. Zerhouni. That was very expository. As a clinical director for the National Human Genome Research Institute and the director of the Intramural Program of the Office of Rare Diseases and an advisor for a number of the organizations that are concerned with rare genetic diseases I have been long aware of the need for an undiagnosed diseases program here at the NIH. Besides providing the hope and information for individuals this program offers unique opportunities for discovery into human diseases. So here are a couple of quick points. As doctors we feel compassion for patients who have been without hope because they are sick and no one has been able to help them. For some this program will offer real hope and maybe even relief. But as Dr. Zerhouni said this is a research program and we won't be able to help everyone who seeks our care. The program's principal mission is the discovery of new diseases and variations of known diseases and many patients applying to this program will present with either known illnesses or problems that no one here is studying. For that reason we've established a fairly stringent referral process to ensure that we have a reasonable chance of helping the patients who do come to Bethesda. So as with all studies at the NIH clinical center the avenue for participation in this undiagnosed diseases program begins with referral from patients health care provider. Patients will not be seen on a walk-in basis. The participants have to be referred by a physician or another health care provider such as a nurse practitioner or a physician's assistant in their own community. Into whose care the patients will return after they're seen at the NIH. The referring physician will have to provide a medical summary and medical tests that point to some clues about what might be wrong with the patient. For example, a patient might have an abnormal lab test, a mysterious x-ray finding or a collection of symptoms that don't usually occur together. Such clues will give the NIH physicians a direction in which to pursue a diagnosis. Then the invitation to participate will be based ultimately on the medical judgment of a board of medical reviewers here at the NIH. That board will have the final say about who's accepted into the program. It will start this initiative slowly. The program is prepared except one or two patients per week and as many as 100 patients during the course of a year. If a patient is selected following physician referral and medical board review he or she will be invited to visit the NIH clinical center. It will be offered enrollment in a study for medical evaluation. The patient will have to provide consent for these investigations. But the care is free for the patient and the NIH will pay for travel and lodging. Patients in the program will be evaluated at the NIH's hospital, the NIH clinical center in Bethesda, Maryland, usually for about a week using the clinical center's unique combination of scientific and medical expertise and resources. Dozens of NIH's senior attending physicians will consult on these cases. Their specialties include rheumatology, immunology, oncology, mental health, nephrology, hematology, ophthalmology, laboratory medicine, neurology, pain and palliative care, bone disorders, endocrinology, dermatology, primary immunodeficiency, dentistry, genetics, pathology, pulmonology, cardiology, internal medicine, pediatrics, and hepatology. If a diagnosis is determined, some treatment options will be explored, but may not always be available. Individuals who are evaluated at NIH as part of this research program will be referred back to their own physician or healthcare provider so that follow-up care is assured. And these cases will contribute to a catalog of descriptive conditions of so-called phenotype atlas for the country. As the experiences of the doctors working with these hardest of cases grow, the team intends to develop a protocol to help other doctors work up a case that is resistant to diagnosis. NIH expects that this program will produce many scientific publications and probably inclusion of new information and textbooks on diagnosis. Finally, some patients will be entered into existing clinical protocols attempting to produce new treatments. Now to put the undiagnosed diseases program in the context of some current related events, I'd like to hand it over to Dr. Brock. Steve? Thank you very much, Bill, and thank you also for your willingness to initiate and lead this project as we start. I also want to thank Dr. Zerhouni and Dr. Gallin for giving us the opportunity to start this pilot project here at the clinical center. One of the most frequent questions and requests that we've received in the Office of Rare Diseases for the past several years relates to the requirements for initiating a study of individual diseases at the NIH clinical center. This protocol and this project will not do this directly but may lead to other clinical trials, clinical studies. Eventually, as more information is gained from the individual patients that enter the study here at the NIH. The Office of Rare Diseases coordinates research and information on rare diseases at the NIH and for the rare disease community. Just before this telebriefing for the media, we had a similar briefing to alert patient advocacy groups about the new undiagnosed diseases program. We are fortunate to have such a strong dialogue with many groups who are able to communicate the goals of this new program to their constituents. We are also seeing an evolution of the role of the patient advocacy groups as funders, in some cases, major funders of research projects, particularly for the rare disorder. So this evolution is occurring and occurring throughout the world as partnerships are being formed globally. This day is also significant. This week, for many reasons, the occasion for this program launch is coincident with a number of other events that are meaningful to the entire rare disease community, included in this is the celebration of the 25th anniversary of the Orphan Drug Act. It is also the 25th anniversary of the establishment of the National Organization for Rare Disorders. This week, starting tomorrow, there is a major conference, an international conference on Orphan diseases and Orphan drugs that will be held in Washington, which will have representatives from over 22 countries that will join us to talk about the various needs and issues related to rare diseases. There is a separate conference being held today on the Orphan Drug Act at 25 years, the retrospective and future views that is being hosted by the Food and Drug Administration, the Office of Orphan Product Development, and the Drug Information Association. Our drug, our genetic and rare diseases information center funded by the National Human Genome Research Institute and the Office of Rare Diseases, reported that approximately 6.6% of inquiries that they received during the past three years were related to an undiagnosed disease. Also from a study done in 1988 with the National Commission on Orphan diseases that approximately 50% of patients received a diagnosis in less than one year. It took another 31% of the patients between one and five years to obtain the diagnosis and approximately 15% of the patients in this study reported that it required more than five years to obtain the diagnosis. And I think everyone can realize the number of specialists, the number of visits, the number of clinics and various trips that had to be made to obtain that diagnosis. And I think the significance of the program is quite understandable. As I mentioned, all the participants will be seen here at the NIH Clinical Center in Bethesda, Maryland. I'd like to ask Dr. John Gallin, Director of the NIH Clinical Center, to speak to us about this facility and the role the clinical center will be involved in the undiagnosed disease program. Dr. Gallin. Thank you, Steve. And I also want to thank Dr. Zinouni for his support in this exciting project and Dr. Gall for helping to lead it. Better health and health care for everyone depends on clinical research. Medical research is the sole mission of the NIH Clinical Center, guiding all of its activity for more than a half a century. The NIH Clinical Center, the nation's clinical research hospital, provides an extraordinary environment for excellence in both patient care and collaborative clinical investigation. The clinical center is the largest hospital in the world, totally dedicated to clinical research. Nearly 10,000 new patients come to the clinical center each year from across the country. Currently, more than 80,000 patients are participating as inpatients and outpatients in nearly 1,500 clinical research studies conducted here. And about half of our patients have a rare disease. Some 1,300 credentialed physicians, dentists, and doctor-prepared researchers, along with more than 1,000 nurses and allied health professionals, work in the clinical center. They care for patients as well as manage and monitor the clinical research studies. About 140 specialized clinical teams made up of dozens of medical specialties see patients at the NIH Clinical Center. This new program will marshal a rich set of skills and expertise already at the clinical center to help patients with unusual medical conditions. Our patients are truly partners in medical discovery. Patients interested in participating in this research program need to discuss the option with their physician or healthcare provider, such as a nurse practitioner or a physician's assistant. Information specialists at the clinical center's patient recruitment call center can provide more information about eligibility and what kinds of medical information referring physicians must submit for review by the program's medical team. The number to call is 1-866-444-8806. The program can also be accessed on the web at http colon to forward slashes rare diseases dot info dot nih dot gov slash undiagnosed. Along the way towards preparing for the launch of this program, various individuals came to mind, the young and the old, who represent the personal aspects of the clinical research programs at NIH. And now this undiagnosed diseases program. One such patient, an extraordinary and courageous young woman who has joined us today to make this announcement is Amanda Young. Amanda Young will tell you the story of what it means to have an unknown diagnosis and what coming to the NIH is meant for her and for her family. Amanda? Thank you Dr. Gallin. My name is Amanda Young and I'm 26 years old and live in Conyers, Georgia with my parents, Susan Lisa Young, and my sister Alex, who are all here with me today. For most of my life, my parents searched for answers to my medical condition that left me vulnerable to life-threatening infection. No one could tell us why these horrible infections attacked my body over and over again. No one knew how to stop them because they didn't understand why I continued to get them. My immune system looked as normal as anyone else was under a microscope except for one small thing, a continuously low white blood cell count. Even after years of trying, no one could give me a name or a reason of why my life was threatened time and time again. By the time I was three and a half years old, I'd had spinal meningitis three times, many seizures, and an abdominal abscess the size of a cantaloupe just to name a few. When I was eight, they had to amputate my leg. It started off as a scratch that I'd gotten while playing, and overnight, the scratch had become infected, and as precaution, I spent a week in the hospital. However, two weeks later, I was fighting to stay alive in the intensive care unit. I developed gas can green and a massive bacterial infection, and I was forced to amputate my leg and hip in the intent to save my life. After this infection, my parents' search intensified as it became even more desperate and determined to find out what was wrong with me. My family and I are able to be here today because of their search for answers that led us here to the clinical center and to Dr. John Gallin. My first visit was in 1990 when I was only nine years old. Dr. Gallin made us a promise, and he lived up to that promise. He told us that he would never give up on me, and he never has. And on May 13, 2003, we received those magical words from Dr. Gallin that we had been waiting 20 long years for. My disease finally had a name. I want anyone who is searching for a diagnosis to be able to experience what my family did that day. It was incredible. All we ever wanted was for my disease to have a name for someone to tell me what was wrong, and Dr. Gallin did that for us. I have an extremely rare genetic mutation. It's called the IRAC4 deficiency. My body doesn't make a certain protein. It needs to fight bacteria, therefore making me a target for life-threatening infections. I haven't had a major infection in several years, which is great. I have to pay close attention to what my body is telling me all the time. I can't let an infection sneak up on me since my body doesn't immediately recognize an infection. I continue to come to the NIH throughout the year depending on my health or if Dr. Gallin needs me for more of his studies. Although my disease has a name now, we don't have a treatment or a cure. So I will continue to come here for my own studies and hopefully help further medical knowledge to help others at the same time. It is great to know that all that they have learned from me could possibly help someone else in this process. That is what this is all about, is helping out each other. If what I have suffered through can somehow help someone else not have to suffer, I am so thankful. The announcement today of the new under-nosed disease program is like handing someone their life back. Everyone who is sick has to have hope to get better and with hope they need help. Dr. Gallin gave us that hope so many years ago and today that same hope is being offered to people just like me all over this country. This is the most exciting news that anyone suffering with an unknown disease could hear. Someone is going to try to help you. Here at the NIH, they have the expertise and technology needed to study rare diseases like mine. And in an odd sort of way, the NIH is like a home away from home for me. And I love Dr. Gallin from the bottom of my heart for all that he has done and continues to do for my family. Thank you all so much for dedicating your time and efforts into this new project. You have not only given people a place to come for help, but you have also given us all a place to come for hope. And I thank you all so much. Thank you very much, Amanda. This is Larry Thompson again. What I would like you to do now is push star one and you can start queuing up to ask your questions. And while you are thinking of what you want to ask and getting into queue, I want to remind everybody that if you don't have the background material or the press release or anything like that, you can call the communications office at the genome institute where operators are standing by. Now, we have somebody standing by the phone at 301-402-0911 and we can send out the long queue whatever it is that you need or else help arrange your interviews if that's also needed. Let's start with our first question from Rob Roar. Tell us where you're from, Rob. I'm Bob Roar, BMJ. You've talked about in terms of national. I just wanted to know if this was also open to patients from overseas, from other countries or not. Dr. Gallin? This is John Gallin. The answer to your question is that the NIH has a long-standing tradition of admitting patients from anywhere. But we only admit patients from abroad if it's a specific protocol and a question that's being asked at NIH that we think can help that patient. Most of the patients for this new program we expect will come from citizens and residents living in the United States. However, if there's a particularly compelling problem that this panel of 25 experts think we can help inform then it is possible for a patient to come here. However, we will only pay transportation for such patients from a port of entry that is once they arrive in the United States. Perhaps Dr. Gallin would like to elaborate a little bit from the perspective of the person who will be running the program. There's just one other issue and that is that when medical records in a case is brought before this panel, the panel may decide that the case is not appropriate for the undiagnosed diseases program, but there may be individual consultants whose area of expertise is related to that patient's case and they may want to bring a person from abroad for their own protocol. Okay, great. Thank you. I'm glad you're ready to identify yourselves in your speaking so that the reporters will know who to quote and quote them accurately. So let's go to Jennifer Cousin at Science Magazine and the rest of you start queuing up with your questions, please. Hi, thanks for taking my question. I understand that patients with undiagnosed diseases are currently treated at the clinical center and I was wondering if you can tell me how many are treated now each year roughly and how that will change under the new program, which I understand can go up to about 100 a year. We see about 10,000 new patients a year and we currently follow over 80,000 patients and roughly about half of those patients have a rare disease. So the net increase in the number of patients followed is not going to be huge. But what is different is that this is the first time we're taking a formal multidisciplinary approach so that every patient is going to really be looked at from the perspective of 25 senior attending physician scientists here who will consider the nature of a multi-system perspective of every problem. And I'm sorry, just to follow up, how is that different if someone contacts you now with an undiagnosed disease and you do accept them to the clinical center? How would their experience be different than it will be under the new program? Currently if a patient calls in their triage to a specific institute and a specific program, so I mean a specific protocol and a specific program and the patient will be assessed by one team. The difference is now they'll be assessed by a large spectrum of teams. Okay, thank you. But actually isn't the, sorry, Dr. Groff, go ahead. Okay, Jennifer, this is Steve Groff, the officer of rare diseases and I think it's important to realize too that to many of the rare disorders involved multiple organs and as Dr. Gall mentioned, multiple systems as well that always don't manifest symptoms at one particular time. So I think what we're trying to do is really to get a little bit better hold on what these symptoms are and try to put all the pieces together with so many specialists involved that can look at all aspects of the disease that's being rejected. Okay, thank you. Well, the only thing to add is, as Dr. Sanhoney pointed out to me, this is John Gallin. Right now the great majority of the patients come to fit into one of the 1,500 protocols. This new adventure will include patients who do not clearly fit into any protocol to see and in some cases we will end up after seeing these patients probably creating new protocols that don't exist. And this is Dr. Gall. So really part of the thrust of this program is to make entry easier so that people in the community and physicians in the community don't have to find their own, the specialist who is interested. This program will triage for them just by making the call and sending in the records. Plus, we have a large group of docs who have already agreed to provide the care for these folks. Exactly. So I'll remind everybody on the phone that if you want to ask a question, you need to push star 1 so that you can get in the queue right now. I don't have anybody in my queue. But let me ask you a question of, well, before I do that, that seems to stimulate some. So let's go to Lauren, your guard from the Associated Press. Lauren. Hi. Just a really quick question about the actual genetic mutation that Amanda Young had. Could you go back and say exactly what that was again and spell it for us? I have the IRAC 4. It's I-R-A-K with the number 4. Okay. And this is a protein in a pathway we call the toe-like receptor pathway which is a pathway that recognizes infectious diseases and patterns of infectious diseases. And it's critical for initiating an immune response to these infections. And Amanda lacks a key protein in the pathway that causes the signaling to occur. And both her parents carry the gene, but they each have a different form of mutation. So Amanda has something called the compound heterozygote where she receives a gene from her mom and her dad and sort of got a double dose of misinformation and that would cause her disease. Her sister is well clinically, but she too carries the same gene that her mom carried. But a normal version from her dad. But a normal version from her dad so she's completely healthy. Lauren, this is Dr. Zerheny. Let me make the point also that at the time Amanda developed her condition, the existence of toe-like receptors in their role in immunity was not known at the time. So it's the discovery of the toe receptors later that then connected the thought in Dr. Galen's team's work with Amanda's potential disease. And this system of toe receptors is really related to what we call innate immunity. This is what the human species has inherited over the evolution to defend itself against infections, which is as opposed to adaptive immunity where you get exposed like a vaccine. And once you're exposed to the agent, then you develop an immunity for it. So the toe receptors were a discovery that occurred after the onset of the relationship between Dr. Galen and Mrs. Young. That's correct. They were actually described in the proof slide first. And then now they're recognized to be very important in all mammal species in addition to the proof slide. I think that's what we're seeing in tomato rare disorders as more and more of the basic research that is conducted and supported. We were getting that translation into the clinical picture. And it's something that years ago we didn't have quite an emphasis on the rare diseases and the research would go so far and then stop. And now we're seeing this translation into the clinical aspects of the patient and knowledge is increasing tremendously with tomato rare disorders. And it's occurring on a global basis, not just here in the United States, but the research partnerships and the patient groups are getting rather extensive and very, very useful as far as supporting research. This is Dr. Galen. I think this program is going to be an illustration of that too because it doesn't go just one way. That is research to translational and patient care. It also goes patients being seen and enlightening us with respect to what the basic defect is and what's going on in terms of the physiology and the cell biology. So we expect this program to contribute to that too. Okay. Okay, Lauren. Thank you. Great. Let's go to Brigid Kuhn, I think, is how you pronounce your last name from Jamin Medical News. Hi. I wanted to just make sure kind of clarify what exactly the program entails. If the patient has an undiagnosed disease, their doctor would refer them and then their case would be looked at by the panel. Is the panel going to diagnose them or just decide if they are qualified? And then if they do get referred to a protocol, what kinds of protocols would those be? Dr. Galen? Well, the panel will review the case and decide if it's eligible to come to the NIH and be part of this program. Okay. After that, the goal would be to make a diagnosis, but that goal cannot always be achieved. So sometimes this will be just, let's say, the foremost evaluation that can be performed by a multidisciplinary group of individuals who can do the clinical research on it. Okay. And the last part was... And if they are referred to a protocol, I mean, do you give an example of what a protocol might constitute for this program? So on this board of consultants are 25 or so individuals who each have their own protocols and their own area of expertise. One of them is expected to take the lead on this, so a patient may be referred to that protocol and enrolled in that protocol, and then other consultants will serve to help come to a diagnosis. As a default, they can come to a protocol that's entitled Inborn Errors of Metabolism, and then basically my service will care for that patient. But I'd like to add that every patient will get an evaluation. And if it turns out that a patient does not seem to fit into a protocol that's at NIH, the physician and the patient will get feedback. So this will be information added to the patient and to the primary care team about what we think might be done or directions to follow or what kind of care to pursue. Okay. That was Dr. Gallin. And Dr. Gallin would like to add? This is Steve. Sorry. I mean, I'm sorry. That's okay. I think it's important to note also, Bridget, that, you know, the referrals can also come in from your nurse practitioners and physician assistants or other healthcare providers that have access to the patient and able to compile a summary, as well as other specialists. I think this is not something that's just puzzling to the family practice or the internist, but many times the individual specialists just don't know where to turn either. And so I think that's part of the significance of this is that we're willing to accept those summaries from any of the groups that I just mentioned. Dr. Zuhuni. Dr. Zuhuni. I just wanted to stress the fact that the reason we're doing this now is because of the advances that have been made over the past five years at the fundamental level. We have many more molecular markers that we discovered, the significance of which is not always understood. It's clear that with the new techniques that have been developed in proteomics and genomics, very few teams in the world have the combination of these new tools to be able to study them in the context of diseases that haven't yet been diagnosed properly. So I think that's the significance of this effort. For the first time, we're going to combine the tools that came out of the labs, like Dr. Galen was saying, tall receptors discovered in drosophilia to human disease. And that bridge could not be really crossed 10, 15 years ago because we didn't have the tools. Okay, let's go back to Bob at the British Medical Journal. Bob? You said the first year or so you would have probably deal with about 100 patients or so. Is there any plan to expand beyond that? And what are some of the barriers that you have to expanding? Dr. Bill Gall. Yes, we'll actually receive a lot more records than about 100 will come to the NIH as our patients. And yes, there will be plans to expand. We hope if this program is well received and we think it is well received. So yes, but we don't know the exact types of patients that we'll be seeing either. So I think that that will in part determine whether or not we expand. We do have capacity for substantial expansion and it really depends on how much interest and how much value we think this adds to the research program. Let's talk to Galen. Anybody else? Okay. Jennifer Cousin again at Science Magazine. Follow-up question? Yeah, I just have two very quick questions. One was in terms of the funding, this is now about $280,000 in funding. Is that per year or total? And then I just wanted to clarify, this is potentially open to patients outside of the U.S. in certain circumstances? Dr. Grossman, I'll take the first one and Dr. Gallan. This is Steve. I'll take the first part. And yes, the total amount is approximately $208,000 from our office, the Office of Rural Diseases. But I think it's important to realize that and that is per year. Okay. Now, for approximately three staff members, two nurse practitioners and a schedule or assistant, but I think it's important to understand too that we're receiving services, both from Dr. Gallan, the National Human Genome Research Institute, and all the other institutes that are providing services of personnel and the intellectual power that comes with it. We're the beneficiaries of an unbelievable system here at the NIS. I don't know if you're familiar, but with rare diseases, particularly significant to be able to pull all these people together at one point to look at individual patients and records to come to some conclusions. Dr. Jones. Sure. The leveraging of all the resources in the intramural program, the clinical resources, which are probably in excess of $900 million a year to make this happen is really what's driving this and the enthusiasm of all the folks. What was the second one? Yeah, Jennifer, it was part two. Oh, I'm sorry. I know you addressed it already, but I was a little confused. Is this open to people outside of the U.S.? Yes, people from outside the United States can apply, but we don't expect that many of them will actually be accepted. But if they have a compelling problem, they certainly will be included. But the travel for them will only be from the port of entry to the United States. We will not be able to travel them from their home country. Okay. And Jennifer, this is Steve again. The enthusiasm and support from those who are in the fellowship training here has been phenomenal. I think they're all extremely interested in this. And again, I can't tell you the number of scientists who they started looking at rare disorders because no one else was looking at them. So whatever we can do to build up that interest and concern and research will be beneficial to all the rare disease as we continue to grow. Okay, great. Let's move on to Jeannie Bauman from BNA. Jeannie? Hi. Yes, I was just wondering, I know you probably can't give an exact time, but how long a patient can expect to wait between the time that they get the physician referral to actually getting into the protocol and how long that time lapse would be? Dr. Gall. Yes, thank you. When we receive inquiries, we expect to send back a postcard and some notifications of the families right off that we've received it or that something's missing. But once we have the whole package together, we expect that within about six weeks, the Board of Consultants reviewing these cases will reach a decision. Okay, thank you. Okay. Let's go to the next question. Mark McCarthy at Medical Device. Medical Device Daily, actually. Sorry, I can only see part of the, thank you. Go ahead. One of the things that occurs to the casual observer is that NIH could find itself pretty overwhelmed with applications, especially in a nation of 300 million. At some point, if NIH is forced to try to prioritize, will the mortality question or speed of mortality take precedence over, you know, perhaps a wider disease more widely distributed, but perhaps not as lethal? I mean, how will NIH go about deciding which cases to prioritize? Well, Dr. Gall, you know, I'm sure that when the Board of Consultants looks at these individual cases that that will be one of the considerations that they look at. But remember, the main point of this is to try to be able to help people, and therefore we need to have some sort of a clue to pursue and some reasonable expectation of benefiting the individual or the family. And secondly, the purpose of this is to acquire new research knowledge. And, you know, imminent death is one of the criteria for the first of those two issues, but not for the second. So I think it will all go in the mix, and there will be some consideration of the issue you raised. But actually, I don't think it will be paramount. Okay. I don't have any other questions in the key right at the moment. If anybody has one, put one in quick, or we could, anybody have any final comments that they would like to make here? And the one question actually that I still had was sort of for Amanda, what was it like to actually come here to the clinical center and receive care here? And we also have Amanda's mother here, Lisa is also here. And she could give us a little bit of a sense of what it's like to be a mom with a small, young child who's sick that you have no idea what's wrong. So, Amanda, what's it like, and then Lisa, if you could just comment on what it's like to come here? I believe it's unlike any other hospital that I've ever been to. Before I came here, I was going to hospitals all over the south and trying to figure out what was wrong with me and just being turned away, time and time again, saying, we don't know what's wrong with you, you're further than metal technology, you'll have to come back later and go home and live a normal life. And it was so hard to hear that, so trying to find a hospital that would actually stick with me and finding the NIH was amazing. And coming here is completely different. The Bedside Manor here is wonderful compared to doctors at home at least. And I love my doctors at home, but I'm glad to know that there's a place that will not give up trying to find out what's wrong with you. If you go to other places and everybody gives up, it's so disheartening. And I love coming here. I love it here. We had one medical facility to tell us at one point your daughter's body is further advanced in medicine. Take her home and live your life as well as you can. And, you know, people at least say thank you and you go on and you start your search again because as a parent, you cannot give up. And when you come here, that hope is renewed again. And to find people who, this is all that they do is they try to research and help and realizing as a parent that if they accept you, hopefully their knowledge and what they gain throughout their knowledge is going to help other people, I think is invaluable to know that things that they may study through Mandi or through the genetic testing that they do with my husband or our other daughter and myself could potentially help other people, I think is invaluable to everyone out there. Not even people who may be sick, but who may eventually have children or grandchildren who are suffering. And it's just a place that we feel very fortunate when Mandi was not into that found. And we've just grown to love it here. It's not always easy to come. It's absolutely a job to take care of a sick child. It's not an easy thing as a parent. And we dedicated our lives, we always tried to say it's not Mandi's disease, it's our family's life. And we hope that through what we've helped her through that we've been able to do that, but it's not easy. And it takes dedication and it takes time. And the fortunate thing here is we feel like as much as we've given, it's been given back to us double. Final comments, gentlemen, ladies. I have no other questions in the queue, so I guess we'll bring this tele-breathing to a close. And if the reporters have any other questions, you can always reach us at the communications office at 301-402-0911 and we'll be happy to help you out. So thank you all for participating, and we'll bring this to a close.