 I'm Max Mönke. I'm a physician, scientist at the National Human Genome Research Institute. I'm the chief of the Medical Genetics branch, which is one of nine intramural branches of NHGII. And I'm the director of the NIH Medical Genetics and Genomic Medicine Residency and Fellowship Programs. I was born in Germany, in Northwestern Germany, in Westphalia, a very small town with a long history, and grew up there until I was five. Then we moved from Westphalia to further north, almost at the North on Sea, almost at the Netherlands border. And that's where I lived from the time I was five until I was six. And then we moved back to the same place. My father was a lockkeeper. So we always lived near a lock. And the lock was always outside of town. So if the town had 500 people where I grew up, then around the lock there were maybe 10 people, maybe two families or three families. My mother was a homemaker. She would make dresses for everyone in town. And she was also the town psychologist. Every woman in town would come to her and would share her problems with my mom. I know my mother. I know my grandmother on my father's side and my grandfather on my mother's side. My father grew up in Pomerania, which is now after World War II Poland. And he was a Lutheran. And then he grew up in a small family where there were many babies born, but they all died. And in the end there were four children who grew up. And my grandfather was blind. He first worked as a forest worker in some duke's forest. And then by the time he was blind, he would raise bees. He could do that while he was blind. And he died on the track from after. He starved on the track from Eastern Germany to Berlin at the time at the end of World War II. And my grandmother made it with her youngest son and my father by that time was a soldier in the war and had corresponded with my mother. That was what young girls were supposed to do then, write to soldiers at the front. And so after the war was over and he was released from being a prisoner of war in an American camp, he was released and he gave the address not as Pomerania, but he gave my mom's address. When he showed up, they were all very startled that someone would really have used the address and show up. And then they started dating and it became clear a Lutheran cannot marry a Catholic, so my dad became a Catholic and they got married. 10 months later my sister was there and five years later I was there. So I think it really planted the seed for appreciation of nature so that I always had my smaller garden that I always had to... That or the other way around that they were not always playmates there. I had to do things by myself and garden was one of them. Getting piano lessons was another one of them, but this was at a time where there was no karate, soccer clubs or any of that, you just had to entertain yourself. And I certainly enjoyed, I certainly enjoyed the various things that I could do from planting plants underground and being surprised that once I dug them back up again that they had lost their green, that they were just white, that they had lost the chlorophyll. It was just fun to see. It was a small school. It was, we were at least with one other grade, so it was first grade and second grade and I think temporarily we were four grades first through fourth grade in one grade. We had children who had various intellectual and physical disabilities in the same grade, became very clear that at age six when I could read and write that I was supposed to and enjoyed teaching someone who was nine years old who was physically impaired. And what I thought was already as a six or eight year old I thought was striking, we had many, many children who were what you call now intellectually impaired at the time the language was not politically correct at all. And they all worked on a farm and it all worked out fine. There was no special at there. And what parents made sure is they felt whether you're intellectually impaired or not, you need a mate and at 16 they found someone who usually was also intellectually impaired and they had many children afterwards. As an eight year old I thought I wonder what those children would be like. And that probably contributed more to my choice of career than any of my nature experiments beforehand. So in Germany at the time that was in the mid 60s you would go either to one school for nine years so that was from first to ninth grade or you would be for four years in that school and then in fifth grade you would go to a gymnasium. And that was for the ones who were better than the others. I say that in quotes and out of my grade out of I forget 30 or so kids there was one that went to gymnasium and that was me. And so going to gymnasium for four weeks it turned out that within four weeks I developed something that most likely was polio and that despite the fact I was polio vaccinated was in a very small children's ward in a hospital in a nearby town and it was striking to me that as a again as a 10 year old or as an 11 year old I could see they did not know what I was having and I was struck by that. I thought, how come you don't know what I'm having? And so I got physical therapy, I got massages, I got water baths, all of the things that I liked but nothing of the Western medicine that we talk about now. I think it had a number of effects since I couldn't turn the page on a book I had to ask the other boys. I was in a what was called the big boys room so there were eight of us there and the big boys room was kids anywhere between 10 and 16 or so. And so I was one of them. So I had to ask them to turn the pages. Someone would come to feed me and I still remember it was striking that if I didn't get the person's attention the fork would go into the cheek or the soup would go down my pajamas. And so I knew from the very beginning to look the person in the eye and talk to her and once I had her attention I would get the food exactly where I had to go. It was very, it was quite intriguing I have to tell you. And so that I was in that hospital for about nine months and then they said, Max is cured except for after nine months when I couldn't walk my parents didn't think I was cured. And then our family physician made sure that I went to a university clinic which was in Münster in Westphalia. And that was quite, that was about a hundred, almost a hundred miles away from where my parents lived. And I was in there then for another eight weeks they diagnosed what it was. There was more physical therapy and then they sent me back home and from then on things started to get better. And what was very clear, something had changed then. I had learned that communication is the most important thing. If you cannot communicate with the other person that you want to talk to, it doesn't help. And that's good for languages. It's good for your own language, for different dialects. It means being present with a person. So that that gave quite an impact. And then the other impact that it had is that even being born in a family where my father would have been proud if I would have become a lockkeeper becoming a physician was something highly unusual. In my family I was the only one who went to college and then to medical school. In Germany, both medical school encompasses college and medical school all in one. So you do everything together. You do gymnasium. And that goes to 13th grade. For me, I was then a year older since I stopped a year and then went back. And I think on a somewhat personal note that had to do with my upbringing when I came back as my sister says I was spoiled rotten. I could ask my parents for any favors and I would get them. And so once I came back out of the hospital I had a dog, I had birds, I had pigeons. I had gerbils, I had golden hamsters, I had mice. I would go along with a dog who would have a pigeon on his back and we would go for walks. It was a little circus scene. But then what I also did to is I was just delighted that I was able to breed mice and to my surprise every once in a while out of two gray mice, they would have a white mouse as an offspring. And I was hoping I could breed white mice because I predicted that they would have white offspring but I never made it to that stage. So that was part of the upbringing in nature. I think the part that I forgot is each year there was a lamb that I would get from the shepherd and I would raise the lamb through the summer. And that certainly felt very special. They're not that many kids who raise lambs while they're kids. Probably would be also smiling of the image of a little muck swatching TV with a lamb on the lap with a feet and watching for shows that the lamb liked the best. And for the lamb like best either Lassie or Fury the American shows. So these were like way back when we were talking in the mid-60s. In Germany there's one central system since in Germany there are no private schools. Every school at the time were public schools and their plus minus all equally good. There is not the harvests of the medical schools and there is not the, I don't wanna put a name to a school that doesn't rank very high. In Germany they're all in the middle to upper third and middle or upper two thirds and so get a good education wherever you go. So I decided to go to Berlin, which was quite exciting coming from a tiny place in Northern Germany going to the big city with over a million people. There was a slight difficulty there. When I got admitted to medical school I was a, in Germany it's, there's a, at the time there was a compulsory army for every young man had to join the army. And I was in the military and of course being an active soldier you cannot, couldn't drive through former East Germany because it was a communist country at the time and West Germany where I come from is a, was part of NATO and all of that. So I had to fly from Hannover to at the time Berlin Templehof. And so then I was in Berlin and was there for seven years and enjoyed it tremendously. And the fact of leaving the military to going to medical school the discrepancy of drudgery to enjoyment couldn't have been and the excitement couldn't have been further apart. It was exciting beyond belief, just exciting to actually do what I thought were real sciences to do chemistry, physics, organic chemistry. And I was just willing to do biology to do medical genetics which we had already as undergraduates. It was just thrilling, just thrilling. And to me in Germany there's something that's called physikum. It's the first major exam that you take for before you start your clinical training. And for me as soon as I had the physikum I could teach the medical genetics class. I could teach students who were just a year behind me and that felt just wonderful. I enjoyed that a lot. One topic was very close to my heart because someone had put me on the right track. It wasn't even genetics, but it was a teratogen. And I'm sure you have heard about thalidomide and thalidomide was a medication that was generated by a German pharmaceutical company and that was sold as a means that was sold against morning sickness during pregnancy. And the connection between the thalidomide or Contagane was the name of the medicine in German and the limb anomalies, both of the legs and the arms where there were shortened limbs almost flipper-like hands depending upon when the medication was taken was identified by a German pediatrician and physician and by an Australian obstetrician. And the German pediatrician was Professor Widokind Lenz who at the time was in the children's work at the Children's Hospital in Hamburg in Germany. And he was an expert in limb anomalies and people from all over Europe would send him their x-rays and he would consult and he would write them back into his surprise for some time he would get one or two inquiries per year out of a sudden he would get two to three per week. And so eventually it turned out what they all had in common was that the moms had taken thalidomide and that happened in the late 50s and early 60s and he was the one to make that connection. And so I had listened to him in Germany as a high school student there was something called Volkshochschule which is sort of the high school for lay people and I went there and so here was Professor Widoman was talking about this and I got so excited that I went to him afterwards and asked how can I do something like what you are doing? And he said, go to medical school, become a pediatrician, go do basic research, do clinical training in genetics and I followed his advice and here I'm sitting, so. And so I taught that and so what I had is in my section on medical genetics it was basic drawing pedigrees, it was basic chromosome analysis, it was taking a family history, it was taking a prenatal history and then it was showing photos, it was showing photos of individuals who have Down syndrome that is chromosome anomalies who had very specific, who had very specific teratogenic anomalies, let's say fetal alcohol, embryopathy who had very typical syndromes and I would talk about all of them as if I had seen them, as if I had known them where I really had seen only photos and read lots of books about it, so. But my interest was really set then as like this is just so exciting, so. What was next was easy because in Germany you do even as a physician you do a thesis and I did the thesis work with the department chairman Professor Karl Spelling at the Free University in Berlin in the Human Genetics Department and mine was on cell cycle regulation and different chromosome, what chromosomes looked like obviously, we all know what metaphase or what metotic chromosomes looked like but then looking throughout the cell cycle in G1S phase and G2 phase and I looked at nuclear law organising regions that are on the aquacentric chromosomes, 13, 14, 15, 21, 22 and it was interesting and before I had finished medical school I had an offer to continue my work there and so then I had a contract as to work at the institute for five years and I left after nine months because I really wanted to work with patients and started then left Berlin after seven years and went to the children's hospital at the University of Kiel in Schleswig-Holstein which is almost which is at the Baltic, is a Baltic harbour almost maybe 40, 50 miles from the Danish border and I did my pediatric residency training there and the chair of that department was another famous geneticist Professor Wiedemann and Professor Wiedemann is in the US syndrome and is called back with Wiedemann syndrome and Europe is called Wiedemann back with syndrome and it's a syndrome where we of course now the underlying causes and it was very interesting to have him as a department chair even though he was Professor Emeritus by the time he changed during my training but he stayed there and so I would see patients with him even after he was Professor Emeritus. Oh, it challenged the sympathetic nervous system it was being on an infant wards for two months when I started in July was fantastic and learning all about middle ear infection, diarrhea, GI issues, all of that that was wonderful but after two months I was on the NICU on the neonatal intensive care unit and that really got my blood and my adrenaline going and it was scary and I was there for six months and after six months I was happy to say that my sympathetic nervous system had calmed down quite a lot, I had learned a lot and then from then on I would be working when I came in in the morning before I saw patients I would go to the cytogenetics lab would do what we call cytogenetic rounds would look at all of the cells would look at all of the amniocytic flasks we did that for an hour and then by 7.30 or 8 o'clock I went to my ward and would see patients there and that was then really for the first time where I would see children who had birth defects of various kinds and many times actually more often than not we did not know what the diagnosis was so this would have been in the early 80s a mere coincidence I had met Dr. Franke at the human genetics meeting that at the time was in Essen and Professor Passage who was the organizer of that meeting had this wonderful picnic and I dared myself to talk to Dr. Franke at the time and she is of course very easygoing what made it particularly easygoing that she's German speaking so I spoke with her and told her of my interest and she said she would be happy to talk to me some more about it then I visited different places in the US and Yale was one of them and out of Minneapolis, Atlanta, Baltimore, Boston I decided Yale and Uta Frankeslab was the best lab for me she is significant for many reasons on a personal level she's just radiant and she is her enthusiasm for work, for patients, for cytogenetics for molecular genetics, is just infectious and then she is someone who has won numerous teaching awards so she has been a mentor for me to be a good mentor she has taught the human genetics class at Yale for years before she then went off to Stanford and taught genetics there taught, was a medical director of the genetic counseling training program at Stanford and I think she has numerous accomplishments and some of them were that Jorge Yunus at the time at the University of Minneapolis and she simultaneously generated the high-resolution chromosomes from chromosomes that were when there were G-banded in, let's say, mid-metaphase they had maybe had a 400-band stage and then the chromosomes that Uta Franke generated had anywhere between 800 and 1,000 bands so in essence it increased the resolution of getting first glimpses at the genome and the talk that she gave in essence at the human genetics meeting in Germany in, I guess it was 1980, was a talk how she had identified various deletions and duplications and patients and her ease of going back and forth between the laboratory and showing patients and the chromosomes and coming up with causes defining minimal critical regions I was in awe of that and I thought, oh, I want to do something like what she does they can pub-met my name at the time since I was set, my wife and I were set to go back to Germany my name was spelled at the time in the German way that is M-U with the two dots, that is the umlaut N-K-E so if you go to pub-met and you search for that you'll find the 10 papers that came out of that time and they were mostly mapping papers and you find chromosomes, DNA and patients all in one paper and to me that was exactly what I wanted to get out of that time and one collaboration was to work with Leon Rosenberg who was at the time the department chair and Jan Krause who was a postdoc in the lab he had identified the gene for homocysteinuria, C-B-S sister-thionine beta synthase and I had the good fortune to map it to chromosome 21 and then to map it to a very specific region on chromosome 21 and that was, I happened to be at the right place at the right time and it was fun, it was just very enjoyable and I met Francis Collins here, I had to my surprise I met all three first year fellows there I'm sorry, the three third year fellows one was named Jake Argus and he is now I'm not sure either in California or at the University West Virginia then there is blanking on his name and then there was someone named Francis Collins and out of the three of them again I was very impressed I was allowed even though I couldn't see patients since I hadn't passed the US exams, medical exams I would sit in the noon conference and Francis Collins would talk about patients he had seen in the morning would give a presentation, an hour-long presentation about a specific syndrome and in the afternoon he gave another hour-long presentation about chromatin remodeling or something that he did in Sherman Weismann's lab and I was, really the word awe is an understatement and so we overlapped for a total of six months I started in at Yale in January of 1982 and Francis finished his three-year training in clinical genetics as an internist in June of 82 before he went on to University of Michigan to become an assistant professor there so yes I've known him, he was one other than Uta Franco was one of the first people I met there actually so it was very clear there was a there was a there was a hierarchy there so there was Francis Collins it became very clear very soon that he had published quite some solid papers with Sherman Weismann and had then continued to publish papers as an assistant professor, papers that are being cited now from cystic fibrosis to neurofibromatosis and so these were not rare disease genes but he worked on common disease genes and was able to identify them so it wasn't just the clarity of communicating a presentation what he has is he had then and obviously has now has a gift of speaking to different to people from different walks of life and to me that has been always important if you can speak to your peers that's that's okay that's a C plus but if you can talk to people from from to people who are non-physicians who are non-geneticists that's a B plus if you can talk to people who are have either who are either Nobel laureates or who are intellectually impaired as and not in the same boat but in the morning in the clinic talk to people who have an impairment and then talk to people who are on the very on a very different end to me that's a gift of communication so that's that is to me the the A plus of communication of what Francis Collins has and and I admire that so Uta Franke being a good mentor she had greased the wheels before I went for the interview she had called two colleagues there at the Children's Hospital of Philadelphia and I never had this feeling ever again that when I walked into the chairman's office my very first interview I knew I had already the job and I could only imagine that was thank you to Uta my CV didn't hurt either but it was really the good mentor who had done that so and of course the prerequisite for that was not only to be able to speak English which I couldn't when I when I came to Yale in 1980 1982 but to also having passed the at the time it was called the EC FMG exams and now they're called the USMLE exams part one and two I had passed those I think in the fall of 2000 of 1985 and then I was admitted to be one first clinic genetics trainees in a July of 1986 it was very different it was it was really one was working just in the lab and visiting the the noon conference at Yale but not being able to be with patients or to see patients and here for the first time it felt I was actually needed at Yale whether I was there or not it didn't quite matter but there was enough drive and enough ambition that it mattered to me at the Children's Hospital of Philadelphia if there was a consult at 3 a.m. in the morning it was clear who had who had to go there if I was a fellow on call I had to be there at 3 a.m. in the morning and it felt really good to be so important that you would show up at 3 a.m. to see this patient in the morning in the NICU and so what in in the training in Philadelphia I think very highly of that training program and that in the first year all you do is you see patients patients and more patients as in an outpatient setting as in patients on the consult service in the biochemical in the metabolism division and the dysmorphology division and so on so it's a very solid foundation of what patients look like and there I actually I got my very first taste for that patients are not all of northern European descent of what I had of course was trained in in northern Germany everyone was fair-skinned, fair hair, light hair, blue eyes and out of the sudden at the Children's Hospital of Philadelphia about half of half people there came were of northern European descent maybe a third of other descent and and probably one third were African Americans and for me this was a very new experience. I mean there I learned at the same time I learned dysmorphology from one of the masters Dr. Elaine Sakai I learned from her oh this is a child with Down syndrome and this is what a child with Down syndrome looks like from this ethnic background and no she did not have to teach me how a child with Down syndrome from northern European background looks like because I knew that and and so I at the same time I didn't learn just dysmorphology in children of of northern European descent I had learned that with Professor Wiedemann in Kiel in northern Germany but with Dr. Sakai it was the patient is there and what comes next and how how does a patient most benefit from your coming into the patient's room talking to the patient's mother parents sometimes grandparents it was very variable anywhere between one and 20 patients so if we were in the craniofacial clinic we would see 20 patients there was a patient every 15 minutes because they came there there's a multi in either the cleft clinic or the craniofacial clinic there's a multidisciplinary approach from speech pathologists to feeding experts to occupational therapists physical therapists neurologists ophthalmologists geneticists were all a team craniofacial surgeons so you would see every patient just for a brief time but over time you would meet them on a monthly basis and so you would get to know them and you would see oh this is what this child looked like before surgery and the surgery looks so amazing that you barely see the cleft of the lip afterwards or the child's face has changed where the shape of the head was very misshapen at birth that after surgery there's a beautifully formed head there of the child with just a minor scar there in Germany people would always think of genetics only as an afterthought and to me it was thrilling how important medical genetics is in the US so for example when a child was born in the middle of the night and this child had multiple anomalies instead of having the surgery already scheduled for the morning the first person other than the neonatologist the obstetrician and the neonatologist who would see the baby was a geneticist and so sometimes it was already based on the fact of looking at the multiple congenital anomalies in the newborn baby there was a very high suspicion this baby may have trisomy 13 this baby may have trisomy 18 we then would at 3 a.m. or maybe by that time it was 4 a.m. do a bone marrow aspiration have the cytogeneticist come in and then with the cytogeneticist confirmation this is trisomy 18 we knew that by 7 o'clock and that had a decision where then the next larger conversation was with the parents do you want a surgery in your child whose prognosis with regards to longevity is very guarded having let's say either trisomy 13 or trisomy 18 and just to see the value of genetics and the impact that genetics can have on decision-making on parents and on the entire and on the entire medical team many times involving ethicists I think is something that I where I really learned begin to appreciate even more not just genetics as a little sideshow to medicine but that it's really this is one of the main players in pediatrics and obviously it has changed now it's a main player in every single specialty so here since since anywhere between two and four percent children newborns have a birth defect some are mild some of them are severe and parents want to know what does it mean for the child how will my child be doing can this be repaired how is my how will my child be doing most important question is always how is my child doing intellectually will my child develop normally and sometimes there are answers sometimes there are not clear answers and the child is a guide and then sometime later not in those first conversations at some point later the child the parents want to know is a genetics could this happen to us again as in what is the recurrence risk if we have another child probably the most important part is to go one step back and actually to just listen and to to even start out with very general question to see what's on their mind and after you have done that a hundred times after you have done that five hundred times or a thousand times there are themes there and themes of concern every parent expects a child that is born normal and every parent expects a child that looks beautiful and if you have a child with multiple congenital anomalies that they're shocked to parents and to just be there and to just see when are parents ready to hear what and i i i think that i find very important the communication with the parents to have a relationship with the parent with the parents that not only is good for that one hour of counseling but that will allow parents to happily come back when they are ready for more questions and whether they're happily coming back is in two weeks or in four weeks or in eight weeks it doesn't matter but it's something i think this first year of life in when a child is born with severe congenital anomalies is very critical to form a bond not to switch health care professionals with follow-up appointments but we have the same health care providers there throughout that year and ideally throughout throughout all of childhood so yes so i uh part of the at the time the way the program at Children's Hospital in Philadelphia worked was the first year you see patients if not 24-7 but all the time and then in your second and third year you have your continuity clinic you participate in conferences and the didactics that is being offered you present patients but then you work in a laboratory and the laboratory that i chose at the time was a laboratory of Bob Nussbaum and Bob Nussbaum at the time was a Howard Hughes investigator and so i was in his lab i had a position that was paid to Howard Hughes and that was wonderful on many levels probably the most practical level i think i got a 100% or a 200% raise in salary from being a clinical fellow to being a Howard Hughes fellow in Bob Nussbaum's lab that was very wonderful having three being married and having three small children so that that certainly was wonderful but i know you're asking about what did i do in his lab and at the time it was quite exciting that Bob had been in St. Louis and before the paper was even out he had learned about cloning in yeast artificial chromosomes and yaks and to me the exciting part was to use to work on yeast artificial chromosomes even though i never made it to the goal and the goal was to clone human DNA and he had generated as a trainee at Baylor he had generated a somatic cell hybrid a human hamster cell line where he had fused human cells from a patient with fragile x and hamster cells and have fused them together had irradiated them and had many times grown them and could show that the fragile site of the fragile x was broken at the fragile site and fused to a hamster chromosome so my easy task was to in my time in his laboratory to generate a yeast artificial chromosome that had part hamster DNA and part human DNA and with a thought that this yeast artificial chromosome would have the fragile site in it as an would lead to the cloning of the fragile x gene that wasn't meant to be but in the process i learned how to clone i learned how to do long-range mapping i learned how to do use pulse field electrophoresis and learned how to make maps that actually were larger than just cloning a plasmid cloning a whatever one kb piece into a plasmid but to have an 800 kb piece in the yeast artificial chromosomes but it all it's not very different from one another it's it's all it's between patients it's between chromosomes and then having extended chromosomes then mapping these chromosomes in somatic cell hybrids in udda francis lab then using at the time there was a method called southern blot analysis from very last millennium and to to learn that and to be proficient at that to finding small pieces of DNA let's say to find a polymorphism one that's 2.8 kb versus 3.4 kb something that could be nice nicely separated on a gel to on a larger gel where you could separate pieces from 10 kb to almost a thousand kb in Bob Nussbaum's lab it's just increasing the the level of analysis by an order or two of magnitude but it's not different it's not out of a sudden doing space science it's doing the same thing just going into more detail and and actually enjoying it tremendously so doing chromosomes in in my class that I gave the medical genetics class as a medical student we would I would draw blood on everyone this would be completely ethically inappropriate nowadays at the time we would I would draw blood on every one of the medical students and then we would analyze their karyotypes and that was considered that was considered standard of practice it was even something wonderful in to do that in a medical genetics course so that every medical that every medical student know his or her chromosomes and fortunately I've done this for four years never have I found anyone who had a different chromosome number than 46 I was very pleased with that so because I could have gotten into trouble way over my ears then Bob was one of the initial branch chiefs here Francis Collins was asked to lead the extramural effort of the genome center at the time he came here and he came here with Jeff Trent as a scientific director from the University of Michigan and one of the first people that hired was Bob Nussbaum as a branch chief and Jennifer Puck as a deputy branch chief and a few other branch chiefs David Ledbetter was a branch chief then in the meantime after I completed my Howard Hughes fellowship with Bob Nussbaum for three years and sitting for my boards and genetics I was offered a position at the Children's Hospital in Philadelphia and and the University of Pennsylvania on the faculty which I accepted in July of 1980 and 1990 sorry and in 1990 I started my lab in part still doing tissue culture and Bob Nussbaum's lab for many reasons one was it was set up number two was it was for free and fetal calf serum is very expensive so Bob was not just a wonderful mentor but he was also very generous and then at some point I forget whether it was year one or year two into my faculty position he said Max I think it's time for you to start your own tissue culture lab which I then of course did so I started the research in my lab on two disorders that were both craniofacial disorders one was a disorder a craniosynostasis disorder and that was called Pfeiffer syndrome and this is a disorder where the sutures of the skull are fused prematurely so that when the baby is born where those sutures are always open so that it makes it easier there can be an overlap of the sutures that the baby can make it more easily through the birth canal sometimes those sutures are fused at birth and the skull is misshapen at birth and at some point needs surgery to to open up those sutures so that was one project and then the other project was a project on the most common anomaly of the developing forebrain and that's called holoprosencephaly and holoprosencephaly is in essence two words prosencephalon is a forebrain and holoprosencephaly means instead of having two brain halves of the forebrain that there's just one single forebrain there so that's holoprosencephaly and so I've studied both of those disorders at the University of Pennsylvania and the Children's Hospital of Philadelphia was on clinical service but I had protected time in the laboratory which I was very grateful for I was very grateful for NIH funding I had a first award I had an NIH R01 award and it was very exciting and then I got tenure and I thought life couldn't get any better and that was pretty wonderful and then I got a call first actually from David Ledbetter to join his branch as an as an investigator and it turned out that was at a time before I had tenure at Penn and I felt if I leave before I have tenure that looks like I was on the verge of not getting tenure so that was not an option and once I did have tenure and I got tenure in 1996 I got another call and I forget whether it was Bob Nussbaum or Claire Franco Manu who was a branch chief of the medical genetics branch at the time and then after some negotiations where things all happened very quickly I joined one year after I had achieved tenure at the University of Pennsylvania came here as a senior investigator in 1997 into the medical genetics branch and actually from day one I became the director of the NIH medical genetics training program I had been the director of the medical genetics training program at the University of Pennsylvania for the three years before and I realized this is something that I really enjoy and people like that and wanted me to do this here as well and I did that here and have been the director of that program for the last 19 years. I think what it really does is I had extremely good mentors Uta Franke, Bob Nussbaum, Elaine Sakai and there are many others that I forget and there are many others either with similar name recognition or less name recognition but these were my direct supervisors, my direct mentors that had quite an imprint on me and to see what their input on my career did to me that was something where I felt if and when I can do that that is very important to me I want to do the same thing and to know that in the since 1993 I have trained close to 200 physicians and PhDs in this training program and see people now be program directors now be department chairs someone somewhere else is very rewarding and medical genetics is still a specialty where there are way too few people who are board certified we need many more so one way of getting more is to train more and to train more so that they train more so it feels it's very rewarding to be on committees where former trainees of mine are running the committee it feels it feels very it feels very good I mean first of all he hired me so that I'm very grateful for since I like this job you can tell I've been here for 19 years and then the other part is he was a very generous person and generous both financially and obviously that's easy at times when there's more money there but also generous with regards to that he would just give broad parameters what he saw as a vision of the intramural program but then really trusted the individual investigator for example me that I would do the right thing so I would come to him and tell him part of the reason to come to the NIH I could have studied craniosynostrosis and total prosencephaly just fine at the Children's Hospital in Philadelphia and the University of Pennsylvania with NIH funding with Hughes funding with other other fundings but I couldn't start a project that I felt I only could do at NIH and that was a project on the genetics of attention deficit hyperactivity which is the most common behavioral disorder of childhood and now we know it's not just in childhood it continues into adulthood so if we find ways of finding causes that lead to either treatments or potentially cures eventually to me that seemed like a very worthwhile goal for a pediatrician like me who is on one hand interested in birth defects and so this is a little different in birth defects that are rare to something that's a behavioral trait and that's quite common and so that was something that I could not do at the University of Pennsylvania so I had applied for grants and they were telling me you don't have enough preliminary data that we trust you you can do that at NIH I could present this as part of my job interview this is what I want to work on and there was some preliminary data there either by my own group and or by others that Francis Collins and Jeff Trent this is something that can be worked on this is a worthwhile goal and we in the genome project can do this better than at other places and that was actually the case so I obviously I can't speak for the leadership I can only speak for myself and I to me what I see I see two major things that if I say cannot be done anywhere else people would argue with me but that where the NIH is in a prime position to do this as part of an informally funded project one is all of the benefits of the close collaboration with the NIH clinical center to me this is a crown jewel of the NIH where we can see patients at the NIH clinical center and work with a blood sample we can do all of the testing and I could give you examples where this has changed the course of diagnostics and treatment of children with a specific disorder where my group and it's not about my group every single other group who has patients at the NIH has done that and will do that in the future that's one part and that if this is independent of healthcare insurance and availability of tests but if this is something that can this is something that can be done here better than at most places the other part is for certain projects that are high-risk high yield sometimes they take longer and they take longer than a funding cycle I still remember my NIH grants were five years nowadays you're lucky if you get three or four years and four years is the absolute luxury and you almost apply you reapply once you're one year into your grant for me to talk about ADHD and the connection to a high-risk project the high-risk project to work on ADHD was very clear to me the more defined the phenotype the better the chance of finding underlying causes for any disorder but ADHD in particular when this is a complex disorder and so what was clear to me is I wanted to decrease the heterogeneity by working with a group of people where ADHD is more common than in the rest of the world and where this is a genetic isolate and I inquired with different genetic isolates and this was a wonderful learning experience in speaking to leaders in the field of the different isolates and it turned out there's a genetic isolate they call themselves the Pisces they live in Antiochia which is a district in Colombia South America where of the small of the local capital Medellin and the Pisces are a highly educated group of people they came some 20 generations ago from the Basque part of Spain and have mostly very little admixture and have been marrying amongst and having families amongst one one another and so what Jeff Trent was able to do he was able on top of the budget for my lab to pay the bill for five years in a row so that we could do the very detailed phenotyping work the very detailed testing work that we needed to do in South America and then get blood samples from almost a thousand people from South America and here we had large families where we had three generations where we had grandparents sipships of anywhere between eight and sixteen where all of these people had children themselves and we could follow ADHD almost like we did in a plain autosomal in a Mendelian segregation and so that was the way how we had the successes that we have had really courtesy of the long-term funding from within the inferno program so so other people have done most beautiful studies on ADHD and you can do many different studies you can do my favorite studies are twin pair studies where you have monozygotic twins so these are twins who have if not a hundred percent but close to a hundred percent of the genetic material in common so this would be just in essence like like one person except for their two and then they of course die zygotic twins and they are as closely related as siblings except for they were in the womb together at the same time so so when you look at those studies the numbers are very consistent that is if you study 100 monozygotic twins where one has ADHD you would expect if it's hundred percent genetics you would expect that every one of the other twins has ADHD as well and the number is more like that if you have a hundred twin pairs out of the other twins anywhere between 70, 75 and 80 will have ADHD as well so in genetics I don't have to tell you this the heritability factor would be somewhere around 70 to 75 percent and that means that three quarters of the contribution to ADHD is genetics whereas one quarter or maybe one-fifth is is environment and to me it's a very so there there many times when you talk ADHD is a very a very likable topic at parties and there are many people how come we have more ADHD now it must be all our living conditions and is it genetics in the first place and those numbers are actually very helpful they calm the discussion they're just the facts it's a little bit like one and one is two it's very straightforward and it takes the emotions out of out of discussions is it genes or environment and the answers yes of course and and so it makes it it makes it much much easier and then the question is what are the environmental factors and then the question is what are the genetic factors and I have my lab has less focused actually not not much at all focused on the environmental factors but really focused on the genetic factors if the child is impaired if the parents feel the child is impaired if the teachers feel the child is impaired if the classmates feel just because I don't want to let this child be part of their group this child is the outsider so if there's impairment there and then there are it's not like you do a chromosome test where you identify a third chromosome 21 like in trisomy 21 but you do this by questionnaires but in the end the above all word word is impairment and if there's impairment there then what can we do to help this family what can we do to help this child and if there is no impairment there then the parents have done a great job and the kid is doing a great job and obviously if you have a higher IQ it gives you a little bit more range of coping mechanisms versus if your IQ is average or is lower and of course ADHD is not attached to any to any IQ and it comes among anyone of off from low IQ to a very high IQ so now we're switching from a complex common trait ADHD to a rare anatomical disorder which is holoprosencephaly so holoprosencephaly starts very early during gastrulation and there are again environmental factors there and there are genetic factors there but these factors have to work as early in humans at day 17 after conception anywhere between day 17 and day 21 day 25 during the after the first three weeks so this is literally speaking just within a week after the last menstrual period is missing and the woman may not know or barely know that she is pregnant that is when when holoprosencephaly starts and even though holoprosencephaly is rare at birth and even rarer as for one year olds and even rarer in adulthood it's extremely common during early pregnancy one in 250 embryos have holoprosencephaly and that's certainly more common than most disorders that there are and since holoprosencephaly is such a severe disorder many times over 90 percent of affected embryos and fetuses are spontaneously aborted so they end up in miscarriages so these babies are not born alive but they are miscarried beforehand and so to answer your question what can we learn by studying a very severe abnormality of the developing forebrain in essence we can study the normal development of the forebrain and what we can study is my lab had identified the first and probably still the most important gene in holoprosencephaly if you have loss of function mutations in a gene called sonic hedgehog then this leads to holoprosencephaly of course the converse is true if you have a normally developed a typically developing brain in humans in mammals in vertebrates then sonic hedgehog is needed during early gastrulation and so I think probably one of the main contributions of my lab is the link that we made between human holoprosencephaly and hedgehog signaling and other signaling pathways that I expressed early during development and what's intriguing even after so this is 2016 the very first patient with holoprosencephaly I saw in September of 1986 so this is his 30th anniversary me seeing that first patient and knowing this is what I want to study and it was very important for me to get a blood sample for this patient's diagnosis but also a blood sample potentially for research after consigned consent forms so what this work really has done is it has allowed us to put signaling pathways together it has allowed us for even using regulatory regions how they regulatory regions on one gene how they interact with another gene for example a regulatory region if it's interrupted by a translocation just separated from the gene coding regions what that is what that means is it's not the gene isn't expressed because it's not started by a by a regulator that can be very far away we could show if this is not activating the gene then the disease can be present and so there's lots of basic science excitement of course some of the work has not only been confirmed but brought much further in animal model systems by other colleagues and it's very pleasing to see how the work between humans and model systems mouse zebrafish fruit fly are all go hand-in-hand of course it makes me smile to know that chris liana nusla and vollhardt and professor wischhaus that they were the ones who identified the head shock gene in the fruit fly and were the Nobel laureates for that so absolutely yes so that we can look at what what we get as a benefit of encode what we get as a benefit of just comparing evolutionary conserved sequences so that we know evolutionarily these sequences in the vicinity of again let me pick my favorite gene sonic head shock are evolutionarily conserved not surprisingly not just among all mammals not just among all vertebrates but going to fish even to the fruit fly and when these evolutionarily conserved sequences are conserved there has to be a reason for it and the reason is many times not always many times that this evolutionary conserved conserved region is a regulatory element for a gene in the closest proximity or very distantly away and both are critical for for expression of this gene so so there is let me make a commercial for it there's a website www.genome.gov backslash atlas and if you go there then you find the project and this is an atlas of human malformation syndrome in diverse populations and it really it started way back when it started maybe in Germany and was carried along but it really had a spark that it was clear we have to have a website at a trip to Nigeria since I mentioned already I worked in the department of Professor Widemann there was an atlas of malformation syndromes that Professor Widemann was a sole author and the photographer was actually not an author but she was highly recognized in this book every single photo in this book was taken by her and every single person was taken for my patient from the clinic and every single patient was of northern european descent and so that was my first experience and I thought everyone was a syndrome with back with Widemann syndrome will look like this everyone with Down syndrome will look like this and so on Turner's syndrome and then when I was in Philadelphia it turned out no this is different what really sparked something different was when two colleagues and I were in Nigeria to initiate a collaboration with Dr. Ekannem Ekure at the Lagos University Teaching Hospital in Lagos Nigeria and she is an outstanding pediatric cardiologist has a busy busy clinic and we were in her waiting area just looking around and the three of us Paul Kuska a family physician and and medical geneticist in the medical genetics branch from the Dr. Charles Rotimi's branch and the three of us were and he is a pediatrician medical geneticist and we were in that clinic and just looking around oh this is it and everyone in this child what they had in common in this practice what they had in common they had a heart effect in common and then we said oh this is a child with Down syndrome we looked at one another and nodded oh this is a child with Turner syndrome nodded this is a child with Noonan syndrome and nodded and this is a child with William syndrome and when we and we all agreed on that and when we then talked to Dr. Ekure and told her oh she knew of course you are these oh they are two children with Down syndrome and then she was surprised wait which one does have Noonan syndrome and which one's has Turner syndrome which one's has William syndrome which one's has deletion 22q11 syndrome she was very surprised and we were equally surprised and just I asked naively has your geneticist your medical geneticist not seen those patients and she just laughed and said we don't have a medical geneticist in Nigeria and so with that it became very clear that even though their heart effects were very well characterized and once we learned what the heart effects were we were a hundred percent sure of our diagnosis because these happened to be the most common heart effect in a child with truncus anomalies in a child with deletion 22q11 syndrome specific heart effects in Down syndrome specific heart effect in Noonan syndrome and so then it became clear that if the child has this fantastic diagnostic tool uh ultrasound cardiac ultrasound EKG and so on and has a very well definition of what the center of what this child's heart looks like but the physician and the parents do not know what the child's underlying diagnosis is it's hard the counseling is very hard so it's very hard to answer questions when parents ask what does this mean for my child does this have intellectual impairment does go with it what's a surgery needed what's a recurrence risk if you don't know the underlying diagnosis it's hard to give a recurrence risk and so then it became clear we need an atlas that has children not just of northern european descent and there are a number of famous atlases around and there was a time when every single patient was of northern european descent the photos are in there nowadays it's probably more like 90 percent of patients of northern european descent maybe 10 percent are from diverse populations and what what the idea was between paul cusca dibo arayamo and myself we need an atlas that focuses specifically on children and adults who do not come from northern european backgrounds because there are many atlases around for for people from northern european descent that's that's when it started and so now took a lot of community building a lot of talking with leaders in the field a lot of talking with sarah hall our bioethicist and the chair of our iab here in of our human subjects committee in the in our institute and eventually there are two papers out there that describe the process the pros and the cons and after very careful weighing both sides it was felt this is a useful contribution that in essence it will help with health care disparities so that not just individuals and people in developed countries who happen to be able to go to a tertiary medical care center where there are is one or several medical geneticists but that even in countries where there is no medical geneticist that either the pediatrician the cardiologist can look and compare facial features with an atlas of children from that same country i think what he has brought is he is one of the few physician scientists who have an equal foot in the lab and an equal foot in the clinic there are very few of them around there are many i heard of statistics that in the Bethesda area one in eight people have a phd in all of Bethesda that's the highest phd rate anywhere in the world at the NIH i'm sure it's one in two people have a phd and probably one in five people have an md phd i'm exaggerating slightly but many of the md phd's even though they are physician scientists they are not as active both as scientists and successful as a scientist as Dan Kasner and equally successful as uh Dan Kasner as a physician and i i am well aware of higher numbers give you a better data but many times the case report the n equal one makes something that persuades you to do something the n equal one for Dan Kasner is a colleague from a country from very far away from the us where this colleague happens to have a very specific disorder that Dan Kasner works on when this person came as a patient to the NIH clinical center i visited her just as a friend and a colleague not as a physician a number of times in the NIH clinical center and she was telling me this was the first time that someone would take this much time with her it was the first time that she got the largest work up ever and it was the first time that the diagnosis was made where then treatment could help her she's back in her home country and is doing all the wonderful things that she does as a physician scientist in her home country and so this n equal one experience is an experience where this friend of mine was telling me as a patient about Dr. Kasner and i find that more convincing than a questionnaire of 100 patients who have been seen by Dr. Kasner so that that to me goes a long way i think over the last probably over the last 10 years there was a push not to neglect ever basic science because really basic science drives translational science at the same time it has been my impression that with all of the work that the genome has allowed us to do the deciphering of the genome that that has done and the continuum work on the genome on understanding it that that has led actually from diagnosis to really treatment and i think the NIH clinical center is one of the premier institutions where you can do those things where you can work not just what brings in money but you can work for on treatment and cures for rare disorders and of course my push would be there to give more funds to the NIH clinical center that there's more support personnel there that there's that the with shrinking our budget that stay the same that the NIH clinical center definitely needs more budget there's no doubt in my mind it goes to expanding the services the the pediatric services we can't have newborns here obviously no one delivers their babies at the NIH and that maybe is better left at outside hospitals but it would be wonderful if we had all the services of a neonatal intensive care unit a pediatric intensive care unit where we could have children who are less than 10 kilograms and who are younger than x number of months here so that would be an expansion which i would very much encourage the leadership of the NIH to do so surprisingly it's still hola prosencephaly there were a number of times when i thought do i stop it and then i sat down very quietly maybe took a silent retreat for a weekend thought about things and in the end came up with the thoughts of at this point we understand half i didn't mention this half of the causes are known and their chromosomal and origin and we know a few other slivers that that explain hola prosencephaly but about two-thirds of those non chromosomal causes we don't know and tell me over the last 30 years we have learned so much and we have certainly more than scratch the surface we have dug in deep but there's way more to find out there two-thirds more of the causes to find out so it's something i feel very strongly about and so doing working more on this and then very carefully consider based on recommendations of the board of scientific counselors or the review committee we just had our quadrennial review and site visit which has gone exceedingly well but also the the site visitors comments were not just insightful they were constructive was really rethinking and reshaping some of the future plans and some of those you cannot do this in a day or a week our site visit was literally speaking two weeks ago so it's something to discuss in detail with other colleagues where can we get the most benefit it's always about how do we benefit the patients how can we get the most benefit for the patients over the next year and whether that is in hola prosencephaly whether that is in ADHD cardiac anomalies or other disorders that we work on in the lab so so part of it is very clear others it's very clear where to work on to get more clarity and i'm grateful to the review committee who actually was instrumental in making some suggestions where to make some shifts and some adjustments and i will not just consider those but i will follow those and come up with a plan not just for the next four years but for the years after that