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  • Christian Schaaf, MD, PhD

Prader Willi syndrome (PWS) results when a set of key genes on chromosome 15 are missing and/or inactive. Figuring out the role played by each of these genes in PWS is a major goal for PWS research. One of the genes in the PWS region is called MAGEL2. Supported by FPWR in two funding cycles, Dr. Christian Schaaf is actively pursuing the question of how a missing — or disrupted — MAGEL2 gene translates into the classic symptoms of PWS and related genetic disorders. Dr. Schaaf is particularly interested in testing the connection between MAGEL2 and autism-like behaviors. We recently had the pleasure of interviewing Dr. Schaaf about his background, research, and focus on PWS.

Dr. Schaaf’s interest in medicine extends back to high school in Germany, and a yearlong class in human biology.  Subsequently, to fulfill his German civilian service immediately after high school, Dr. Schaaf worked for the Red Cross for 15 months in emergency medical training, truly enjoying the experience. In medical school at the University of Heidelberg, he realized his love for pediatric medicine, and in solving medical mysteries, investigating cases where others hadn’t found the answers as to what was wrong. He witnessed the frustration and anxiety of parents not knowing why their children were ill, and the satisfaction in figuring out the causes of mystery illnesses, leading to effective treatments.

During medical school, Dr.Schaaf did research in a lab focusing on cancer genetics, and obtained a combined MD and PhD degree. He also had a unique opportunity, through a scholarship from the Foundation for German Business, to travel to and train in New York, Toronto, and Tasmania. During his final year of medical training, Dr. Schaaf did a 4 month rotation at Baylor College of Medicine in Houston, engaging in a mixture of clinical and research work. Here, he deeply appreciated the fact that the department was equally strong in both clinical and research approaches, that there was significant collaboration within the department, and a direct translation between basic research and clinical applications (i.e., both “bench” and “bedside” work). At the end of 4 months, he was hooked on Baylor, and decided to do his medical residency there. Dr. Schaaf was a resident at Baylor from 2006-2010, after which he became an assistant professor (tenure-track since 2013). He currently holds the title of Assistant Professor of Molecular and Human Genetics at Baylor, and his lab is located at the Neurological Research Institute of Texas Children’s Hospital, where he is an Investigator.  He is also the Chair of the Education Committee of the American College of Medical Genetics, and has written a textbook for human genetics, called “Human Genetics: From Molecules to Medicine.”

Research in Dr. Schaaf’s lab is devoted to understanding the genetics of neurodevelopmental and neuropsychological disorders including those related to autism. Dr. Schaaf uses mouse models to pursue these questions, as well as generating stem cells with particular genetic profiles (i.e., deletions, mutations), which can then be programmed to become a particular type of cell. He and his research group also collect data directly from patients affected by genetic disorders. There are a few genes in particular whose role in neurodevelopmental disorders Dr. Schaaf is currently studying. These include the genes, CHRNA7, NR2F1, and MAGEL2.

Dr. Schaaf’s study of the MAGEL2 gene is extremely important for advancing our understanding of the genetic basis of PWS and related disorders. He came to MAGEL2 research almost by chance when a patient was referred to him with an indication of autism spectrum disorder (given Dr. Schaaf’s longstanding interest in autism genetics). Furthermore, the patient showed some of the symptoms of PWS, but standard genetic testing for PWS was negative. The patient was then revealed to have a so-called “truncating point mutation” in the MAGEL2 gene. A point mutation consists of a substitution, insertion, or deletion of a single base pair. In the case of a truncating point mutation for a protein-coding gene like MAGEL2 (which leads to the synthesis of a protein when functioning normally), the mutation disrupts — or truncates — the process of protein coding, i.e., the very function of the gene.  Dr. Schaaf then found 3 more cases of patients with similar truncating point mutations in MAGEL2, with very similar associated “PWS-like” clinical symptoms. However, there are some important differences with respect to PWS that are associated with the MAGEL2 point mutation, including problems with joint contracture (tightening), and a much higher rate of autism spectrum disorder. These distinctions eventually led to the disorder arising from MAGEL2 point mutation receiving a separate title; it is now called “Schaaf-Yang syndrome,” after Dr. Schaaf and Dr. Yaping Yang, who directs the Whole Genome Laboratory at Baylor (whose database was crucial for identifying additional cases of MAGEL2 point mutations).

Dr. Schaaf and his lab are currently considering the question of MAGEL2 and PWS from multiple different angles. They are using genetically altered mice lacking the MAGEL2 gene, systematically evaluating the behavior patterns of such mice in direct comparison with those of genetically normal mice, and searching for signs of autism-like patterns in the MAGEL2-deletion mice. They are also conducting a comparative study of the behavioral, cognitive, and hormonal profiles of 10 human patients with point mutations in MAGEL2, along with those of individuals with classical PWS. This comparison will highlight the specific role of MAGEL2 in the symptoms of PWS — just as studies of patients with microdeletions of the SNORD116 gene alone demonstrated the importance of that gene in the manifestation of hyperphagia.

One important discovery is that MAGEL2 mice appear to be deficient in oxytocin, a hormone whose deficiency in individuals with PWS has been linked to a wide range of behavior problems. Disruption in the expression of MAGEL2 may lead at least in part to oxytocin problems in PWS. Dr. Schaaf is therefore extremely optimistic about ongoing and planned oxytocin trials for the PWS community, and sees oxytocin treatment — especially during infancy — as a key component of treating the behavioral challenges associated with PWS.

FPWR has had an important impact on Dr. Schaaf’s research, providing not only financial support, but also connecting him with other top researchers in the field of PWS research. He has particularly appreciated his interactions with Dr. Rachel Wevrick, Dr. Maithe Tauber, Dr. Jennifer Miller, Dr. Marc LaLande, Dr. Francoise Muscatelli and Dr. Rudy Leibel, some of whom he met at a recent FPWR research conference.

Outside the lab, Dr. Schaaf and his wife keep very busy with their family of three (soon to be 4) children, all of whom are 5 and under! Dr. Schaaf enjoys the outdoors, including hiking and skiing in the mountains, which he misses a little bit, living in Houston. He also enjoys riding his bike to work every day.

  • Carrie Bearden, PhD

Behavior and mental health issues are an important part of Prader-Willi syndrome (PWS). In particular, one of the most challenging aspects for families to face is the onset of psychosis (i.e., mental illness characterized by symptoms, such as delusions or hallucinations, that indicate an impaired contact with reality). Recognizing the early — or “prodromal” — signs of psychosis can be a very effective path to intervention and treatment.

While relatively new to the PWS community, Dr. Carrie Bearden has extensive experience studying the causes of psychosis in neurodevelopmental disorders, and has recently been funded by FPWR to identify these early signs of mental illness in PWS. We recently chatted with Dr. Bearden about her background, research, and perspective on PWS.

Though beginning her college career as an English major and feeling torn between the studies of science and literature, Dr. Bearden was drawn to the field of psychology after taking an introductory psychology class. A class on developmental psychopathology — i.e., the study of brain development and psychological disorders — convinced Dr. Bearden that she wanted to go to graduate school in psychology. As an undergraduate, she conducted research in a few different labs, most notably one in which she studied the emotional and physiological reactions of couple during conflict (one of her responsibilities was to talk to the couples in such a way as to provoke conflict).

After college graduation, Dr. Bearden received a Mellon Fellowship to study at the Western Psychiatric Institute and Clinic in Pittsburgh, and did an internship studying dolphin communication at the Kewalo Basin Marine Mammal Laboratory at the University of Hawaii. She then started graduate school at the University of Pennsylvania, studying the biological basis of schizophrenia, building on her interest in using psychiatric disorders to understand the brain, and the biological basis of behavior. Following graduate school, Dr. Bearden did a clinical internship at the San Diego VA Medical Center and Child Psychiatry Inpatient Unit, and postdoctoral fellowships at both the University of Pennsylvania and UCLA before joining the faculty of the Departments of Psychiatry and Biobehavioral Sciences in the Semel Institute for Neuroscience and Human Behavior, and the Department of Psychology at UCLA. At UCLA, she also directs the Center for the Assessment and Prevention of Prodromal States (CAPPS) program and the Adolescent Brain-Behavior Research Clinic.

Dr. Bearden’s lab studies the causes and underlying physiological mechanisms of psychosis, using a variety of approaches. These include neurobiological techniques such as brain imaging and the measurement of hormone levels, molecular biological methods such as finding the links between specific genes and their expression in mental illness, and clinical approaches based on the analysis of responses to surveys that identify risk factors for mental illness. Genetic disorders with an increased instance of psychosis provide great test cases for understanding the factors leading to mental illness.

While still in graduate school, Dr. Bearden was first introduced to 22q11.2-deletion syndrome, a genetic disorder that results in some common behavioral problems, and an increased risk of psychosis. She performed psychological assessments of children with 22q-deletion syndrome as part of a large project on the syndrome being performed at Childrens Hospital of Philadelphia. Studying the onset of psychosis in 22q-deletion syndrome remains a focus in Dr. Bearden’s lab today. Another genetic disorder that the Bearden lab investigates is Neurofibromatosis I, which is commonly associated with cognitive problems and learning disability.

Dr. Bearden was invited to attend the FPWR Mental Health Research Strategy workshop in March, 2015, as an expert on psychosis related to genetic disorders. At this meeting, Dr. Bearden participated in many stimulating discussions about how to develop the optimal tools for characterizing psychosis in PWS in a systematic fashion, and fully utilize the information collected in the Global PWS Registry. For example, anecdotally, psychosis in PWS often seems to manifest in brief intense episodes, and be associated with extreme mood swings; but how can we predict the onset of such episodes? Following the FPWR workshop, Dr. Bearden identified the need to conduct a systematic survey project to characterize the early (or “prodromal”) signs of psychosis in individuals with PWS. In this pilot project, recently funded by FPWR, Dr. Bearden and her group will study 50 individuals with PWS over an age range of 12 to 50.

The project is titled Predictors of psychosis in PWS. These individuals (or their caretakers) will complete carefully designed surveys geared to find the early signs of psychosis (example survey items to agree/disagree with include, “I see things other people don’t see”, and “I see visions”), and those that probe memory, verbal and non-verbal reasoning, emotion recognition, and processing speed. Participants will also provide saliva samples that will be used to measure the levels of hormones such as cortisol, for which an elevated baseline level appears to be associated with a higher instance of psychosis. DNA will also be extracted from saliva samples, for future analysis and association with signs of mental illness. The data collected for this project will be used to understand the multi-dimensional factors leading to psychosis in PWS, and to provide a baseline cognitive description of individuals with PWS who have not yet experienced psychosis.

Identifying the prodromal signs of psychosis in PWS will enable early intervention and treatment, which has been shown to result in better mental health outcomes. In addition to anti-psychotic medication, Dr. Bearden has hope for multiple forms of non-pharmacologic treatment, which include family therapy focused on stress reduction, vagus nerve stimulation, and cognitive behavioral therapy. The results from Dr. Bearden’s pilot study will pave the way for a larger prospective study, and transform our understanding of mental illness in PWS.

Outside the lab, Dr. Bearden loves spending time with her family, including her husband, who is also a psychologist, and her son (13) and daughter (10). Dr. Bearden’s family loves to travel together, and to sample the wide variety of cuisines that can be found in Los Angeles.

  • Janine LaSalle, PhD

Sleep disorders are common in Prader-Willi syndrome (PWS). These are associated with central and obstructive apnea, disrupted sleep, and excessive daytime sleepiness. But why exactly do individuals with PWS have abnormal sleep patterns? Dr. Janine LaSalle has uncovered an exciting new link between the missing genes in the PWS region of chromosome 15, and genes that control our circadian rhythms (i.e., our daily sleep-wake cycle). This intriguing discovery opens the way for new therapies to regulate sleep and metabolism in PWS, which Dr. LaSalle is currently investigating with support from FPWR. We recently spoke with Dr. LaSalle about her background, the current research in her lab, and her outlook on PWS.

Drawn to math and science in high school, Dr. LaSalle was a pre-med student at Randolph-Macon College until a summer research experience studying the disease, lupus, turned her on to the idea of pursuing a PhD in immunology. After obtaining her PhD at Harvard University, Dr. LaSalle was a postdoctoral researcher in the lab of Dr. Marc Lalande (another FPWR-supported researcher) at Harvard Medical School, switching fields to the area of epigenetics. Epigenetics is the study of changes in gene expression (i.e., translation of genes into observable traits) that do not arise from changes in the sequence of DNA itself, but rather are due to changes in the chemistry surrounding the DNA molecules. The imprinting, or silencing, of the maternal genes in the PWS region is a textbook example illustrating the role of epigenetics. Dr. LaSalle found the ideas of epigenetics to be fascinating, that there is more to one’s destiny than simply the sequence of base pairs in one’s DNA, that it matters if certain genes come from one’s father or mother, and that certain genes are turned on an off through a process called methylation.

As a postdoc, Dr. LaSalle already began studying the epigenetics of Prader-Willi and Angelman syndromes. She has continued this focus as a faculty member at the University of California, Davis, where she is a Professor in the Department of Medical Microbiology and Immunology, and member of the UC Davis Genome Center and M.I.N.D. Institute. Dr. LaSalle’s lab currently studies the role of epigenetics in several neurodevelopmental disorders including Rett syndrome, PWS, Angelman syndrome, and autism. FPWR has supported Dr. LaSalle’s research in two grant cycles, providing key pilot funding that has been critical for obtaining the important initial scientific results that are required for a successful grant from the National Institute of Health (NIH). The hallmark of Dr. LaSalle’s research is observing the processes of gene expression “in action” in cells.  In one FPWR-supported study, Dr. LaSalle and her group investigated the detailed mechanisms of gene silencing and expression in the PWS/Angelman region of chromosome 15. They specifically studied the effect of a chemotherapy drug, topotecan, on the expression of the gene, UBE3A, which is one of the key deleted/silenced genes in Angelman Syndrome. In this work, Dr. LaSalle and her group highlighted the importance of molecular DNA+RNA structures called “R-loops” in the regulation of UBE3A’s expression. More recently, Dr. LaSalle and her lab have discovered an intriguing link between another key PWS-related gene, “116HG” (part of the SNORD116 gene), and circadian rhythms in a mouse model of PWS. Based on their experiments, Dr. LaSalle and her group find that the 116HG gene regulates the expression of other genes that control circadian rhythms and metabolism.

The lack of 116HG in PWS cells leads to a disruption of metabolic processes related to the sleep cycle, which may explain the sleep problems experienced by individuals with PWS. There may be broader implications as well, as Dr. LaSalle points out that the regulation of appetite (another major issue in PWS) may be linked to our circadian rhythms.  What is very exciting is that the drug, rapamycin, may work to regulate the circadian-rhythm genes, in the absence of 116HG. Dr. LaSalle is currently testing this hypothesis on mice, with hopes of translating the therapy to humans.

Dr. LaSalle has found it very inspiring to meet PWS families in person, and is looking forward to attending the IPWSO conference in Toronto this summer. She feels that it is a truly exciting time in PWS research, because there are many existing drugs that can be repurposed to treat PWS. The specific example that Dr. LaSalle is considering at the moment is rapamycin, a drug used to prevent organ transplant rejection, which she has been using (as described above) to address sleep disorders in PWS.

Outside of the lab, Dr. LaSalle stays busy keeping up with her two teenage sons. Her older son, a serious gymnast, just finished his junior year in high school, while her younger son, who is 13 years old, plays three sports. Needless to say, there are lots of afterschool sporting events to attend!

  • Lawrence Reiter, PhD

You may have noticed a recent announcement from FPWR requesting your child’s lost baby teeth. What can these baby teeth do for Prader-Willi research? The answer is that Dr. Lawrence Reiter has implemented a novel technique for studying the genetics of Prader-Willi syndrome (PWS) based on special stem cells contained in the interior of teeth, research that has been funded this past year by FPWR. We spoke with Dr. Reiter recently about his work and life, and learned all about the exciting research he is conducting using teeth to decode the workings of PWS.

Dr. Reiter became interested in biology back in high school, studying Drosophila melanogaster (i.e., fruit flies) in his Advanced Placement Biology class. His sense of innovation was evident even at this early stage, when he designed tiny rafts to save the flies from drowning in the wet, mushy food on which they were grown. He was exposed to molecular biology in college at the University of Southern California, where his study of Drosophila continued in the lab of Carol Miller, this time in extracting a protein from fly heads that reacted with a particular type of antibody. Out of college, Dr. Reiter volunteered as a teacher in New Orleans for Teach for America, and then got a job as a technician in a lab at LSU Dental School (perhaps planting the seeds for his future research on teeth!). During graduate school at Baylor College of Medicine in the Department of Molecular and Human Genetics, Dr. Reiter used DNA sequencing methods to study the detailed molecular processes that cause Charcot-Marie-Tooth (CMT) disease. This genetic disorder results from a duplication on the 17th chromosome, which manifests as problems with the peripheral nervous system (just to clarify, in this case “Tooth” is the last name of one of the co-discoverers of CMT). It was during graduate school that Dr. Reiter was first exposed to PWS and Angelman syndrome, at a weekly departmental seminar run by one of his professors, Dr. Arthur Beaudet. For his postdoctoral research at the University of California, San Diego, Dr. Reiter returned to the study of Drosophila, this time as a genetic model of human disease. Indeed, 75% of the genes that cause disease in humans have analogs in the DNA of flies.

Currently, Dr. Reiter is an Associate Professor at the University of Tennessee Health Science Center (UTHSC), and the Director of the 15q Duplication Autism Clinic at Le Bonheur Children’s Hospital. He runs a lab that focuses on the molecular basis of genetic disorders of the 15th chromosome. Most of his prior experience has been with Angelman and 15q Duplication (dup15q) syndromes. Angelman syndrome is the mirror of PWS, in that it occurs when maternal DNA on the 15th chromosome are missing either through a deletion or uniparental disomy of the paternal chromosome. Dup15q syndrome is found in 3-5% of autism cases, making it the most common chromosomal abnormality associated with autism spectrum disorders (ASD). Over the past few years, Dr. Reiter has turned his attention to PWS, a natural extension of his past chromosome 15 research. Furthermore, he is exploring the connections between genetic disorders and autism, which is an important area of study for our community, as many individuals with PWS display some of the characteristic features of ASD.

And now, about those teeth and PWS: Several years ago, Dr. Reiter was attending the International Meeting for Autism Research (IMFAR). At the time, he was very interested in studying brain cells affected by genetic disorders, and searching for new techniques to generate such cells in the lab. A friend at IMFAR suggested the possibility of synthesizing brain cells from the stem cells found in the dental pulp of teeth, i.e., Dental Pulp Stem Cells (DPSCs). (Recall that stem cells are special cells that can differentiate into specific types, including brain, muscle, and blood cells). There are other techniques for generating PWS brain cells, which consist of taking skin cells from individuals with PWS, transforming them into stem cells, and then making brain cells from the “induced” stem cells. The DPSCs provide a more direct channel to brain cells, however, as that first step of transforming into a stem cell is not necessary. After generating the PWS brain cells (neurons) in a dish, Dr. Reiter and his group are performing a close comparison of the way in which genes are expressed (i.e., translated into observable traits) in both PWS cells and control sample of non-PWS cells. Details on the project can be found here. Specifically, it is known that the SNORD116 gene is one of the most important genes missing in individuals with PWS. However, Dr. Reiter plans to study how the lack of SNORD116 affects the expression of additional genes in neurons, drawn from both the PWS region of chromosome 15, and throughout the rest of the human genome. One unique aspect of this research is the goal of studying the difference in gene expression not only between PWS and non-PWS neurons, but also between PWS and PWS+ASD neurons (i.e., between cells drawn from individuals who have PWS both with and without the symptoms of autism). Given the novelty of using DPSCs to generate PWS brain cells, funding from FPWR has been crucial for generating initial results that can then be used to obtain funding from major agencies such as the National Institute of Health (NIH).

Dr. Reiter feels that characterizing gene expression in PWS brain cells may have real promise for future drug therapies. Specifically, one type of treatment based on “antisense oligonucleotides” can regulate the amount of expression of particular genes. Such exciting new therapies might be well-suited to PWS, once we understand exactly how genes are expressed differently in PWS and non-PWS cases. In his research, Dr. Reiter is thrilled to collaborate with Dr. Stefan Stamm, another FPWR-supported scientist. He is also incredibly grateful to all of the PWS families who have contributed baby teeth. Without these teeth, he would not be able to perform the amazing analysis described above. So, keep sending in those baby teeth, click here for more information!

Outside of work, Dr. Reiter and his wife love to travel. They have particularly enjoyed trips to St. Thomas and Aruba. Another hobby is rum. Therefore, one recent travel highlight consisted of visiting a 400 year old agricole (cane juice rum) distillery in the British Virgin Islands. Dr. Reiter also loves riding and refurbishing old motorcycles, and currently has 15 of them! Finally, one great pleasure for Dr. Reiter is watching his 10-year-old son play baseball.

  • Marc Lalande, PhD

Prader-Willi Syndrome (PWS) most commonly results when a set of key genes are missing on the paternal 15th chromosome (deletion) — or else when the paternal chromosome has been entirely replaced by a maternal copy (uniparental disomy, UPD). One of the most frustrating aspects of PWS is the fact that perfectly reasonable versions of the missing 15th-chromosome genes exist — i.e., the maternal copies.  This is true whether PWS arises by deletion, UPD or an imprinting mutation.  However, regardless of the genetic mechanism causing PWS, these maternal genes are silenced, so that they do not perform thefunction of the missing paternal genes. What if it was possible to activate the silenced maternal genes? Such activation is the goal of Dr. Marc Lalande’s research, which has been supported by FPWR in three funding cycles.  We recently chatted with Dr. Lalande and learned about his life and career, and some of the fascinating techniques that he and his lab are using to recover the function of these silenced maternal genes.

Dr. Lalande’s early background is somewhat unconventional compared to those of other leading PWS researchers. He obtained an undergraduate degree in Physics from Laurentian University in Canada, and even worked as a meteorologist for a few years. He then switched gears, deciding to attend graduate school in medical biophysics at the University of Toronto. Following his PhD, Dr. Lalande moved to Boston as a postdoctoral researcher at both Harvard Medical School and Boston Children’s Hospital. After a three-year stint as an Assistant Professor at McGill University, Dr. Lalande moved back to Harvard Medical school as an Associate Professor and Assistant Investigator at the Howard Hughes Medical Institute. Since 1998, he has been at the University of Connecticut, where he is currently the Chair of the Department of Genetics and Genome Science, and the Director of the University of Connecticut Stem Cell and Systems Genomics Institutes.

Dr. Lalande’s route to studying PWS began in graduate school, where he helped to design an instrument to sort cells into different types using fluorescent dyes. He used this technique to study how white blood cells in our immune system work. Dr. Lalande’s research on cell sorting prepared him for work as a postdoctoral fellow separating chromosomes and studying their DNA content. Notably, these studies included chromosome 15, which contains the PWS region. Over the past three decades, Dr. Lalande has played a leading role in forefront studies of the genetics of PWS and Angelman’s syndrome, both of which result from the disruption of a particular region of chromosome 15.  Perhaps most importantly, these studies include the discovery that genetic imprinting, i.e., the silencing of maternal [paternal] genes in the case of PWS [Angelman’s], is one of the basic processes underlying PWS. Imprinting is a normal genomic process, but the problems associated with PWS most commonly arise when the activated paternal copies of certain genes on the 15th chromosome are missing (either through a deletion on the paternal chromosome, a duplication of the entire maternal chromosome 15, or a specific mutation  disrupting the imprinting process), leaving only the silenced maternal copies.

Over the last several years, Dr. Lalande’s research on PWS has focused on a couple of key directions, which have been supported by FPWR. First, the Lalande lab has worked on techniques for taking skin cells of individuals with PWS, programming them to become stem cells, and then generating neurons (i.e., brain cells). These artificial PWS neurons play a key role in developing a good stem cell model for PWS and in understanding what is different about brain cells in individuals with PWS. The PWS neurons will also be crucial for figuring out how to turn on the silenced, or “imprinted” maternal genes underlying PWS.

Determining how exactly to activate the imprinted maternal PWS genes constitutes another major focus for Dr. Lalande’s lab. Central to this question is understanding how the maternal genes are switched off in the first place. Along these lines, Dr. Lalande and his group have identified a certain protein, ZNF274, which plays an important role in silencing maternal genes in the PWS region. Their goal is to understand what happens if ZNF274 is either destroyed or otherwise prevented from attaching itself to the chromosome near the PWS region, since the binding of ZNF274 to the sites of PWS-specific genes appears to cause the genes’ imprinting in brain. In this research, Dr. Lalande and his group are attempting to activate the maternal DNA in the PWS neurons that they’ve generated from stem cells. Based on these experiments, Dr. Lalande hopes to understand how exactly the switching on and off of maternal genes works, and what subset of PWS genes can be switched on by interfering with ZNF274.

Ultimately, Dr. Lalande hopes that his experiments with ZNF274 and PWS neurons will lead to therapeutic approaches for PWS. Important challenges include figuring out which time (i.e., which developmental stage) is best for gene activation, and also how best to implement the gene activation in humans (i.e., through the development of effective drugs). Although it is very expensive to develop stem cell models for PWS, and extremely challenging to sort out the complex genetics associated with this disorder, the potential pay off for treating — or even curing — PWS is huge. Dr. Lalande is very optimistic about the future of PWS genetics research. In particular, he feels that recent developments in generating human stem cells and gene editing will have major impacts on the health of those with PWS. He has also been very motivated in his research by meeting the families of individuals with PWS, and heartened to see so many families coming together to support a common cause — i.e., PWS research.

Working in the lab and leading the Stem Cell Institute and Genomics and Personalized Medicine Program at the University of Connecticut keep Dr. Lalande very busy. Outside of work, though, he loves spending time with his family, including his two grown children who both live fairly nearby, and, most importantly, his two grandchildren.

  • Kate Woodcock, PhD

Prader-Willi syndrome (PWS) is an extremely multi-faceted disorder. In addition to a wide variety of medical challenges faced by individuals with PWS, and feelings of constant hunger, behavioral problems are quite common. These include temper outbursts, meltdowns, and a rigidity of perspective.  Dr. Kate Woodcock is the recipient of two recent grants from FPWR, whose goal is to understand why individuals with PWS have such problems with emotional flexibility, and develop methods to help these individuals move beyond their behavioral issues. We recently had a chance to chat with Dr. Woodcock about some of the novel approaches she’s using to help those with PWS, and learn more about her background and outlook.

Dr. Woodcock is currently a Lecturer in Psychology at Queen’s University Belfast, where she has been on the faculty since 2014. Previously, she received her PhD from the School of Psychology at the Univerisity of Birmingham, did postdoctoral work there at the Cerebra Center for Neurodevelopmental Disorders, and was then awarded a Marie Curie Fellowship to conduct research both at Peking University in China and the University of Birmingham. Ever since high school, Dr. Woodcock has had a strong interest in science wedded with a passion for helping people in need. As a discipline, psychology satisfies both of these interests. During graduate school, Dr. Woodcock gained her first serious exposure to behavioral disorders related to genetic syndromes when taking a fascinating course taught by Professor Chris Oliver, who subsequently became one of her PhD supervisors. Dr. Woodcock was also drawn to the interdisciplinary perspective required for studying genetic disorders, spanning from the clinical (i.e., medical) to the cognitive (i.e., basic brain research).

Dr. Woodcock started studying behavioral issues in individuals with PWS during graduate school, devoting her doctoral thesis to understanding temper outbursts in PWS. She has subsequently investigated behavioral problems associated with several different developmental disorders in addition to PWS, and tried to characterize the factors in the brain and surrounding environment that control our emotions. Dr. Woodcock’s research continues to focus on understanding and treating behavior problems in individuals with genetic disorders.

With support from FPWR, Dr. Woodcock is studying something called “task switching,” also referred to as “attention switching.” Task switching is a process in which our brains shift attention from one type of task to another. The ability to switch tasks on a basic brain level has been shown to be impaired in individuals with PWS, which may be linked to everyday inflexibility and difficulty in deviating from a rigid routine. Dr. Woodcock and her group have designed a novel video game, called TASTER (Training Attention Switching for Temper Episode Reduction; http://tasterproject.com/about/), during which the player (i..e, a child with PWS) is faced with various challenges, such as collecting objects of a particular shape or color, while at the same time avoiding hazardous elements, such as falling boulders. The common theme is that, at certain points during the game, the player is required to stop performing a certain task and start performing another one.  In developing the TASTER game, Dr. Woodcock and her postdoctoral researcher, Dr. Nigel Robb, have tried to optimize the conditions leading to an improvement in task switching, and, ultimately, behavior patterns. These include the fact that multiple activities happen simultaneously (to mimic real life), that graphics music and subject matter are tailored to players’ preferences to maximize their motivation for playing, and that the game is adaptable, getting more challenging as the player engages and becomes more adept. One key element of Dr. Woodcock’s research is finding PWS families to participate in the TASTER project, and she has been glad to find volunteers through PWS family support groups in the UK, USA, and Canada.

Another one of Dr. Woodcock’s current projects is called PREDICTORS (Parent Resource for Decreasing the Incidence of Change Triggered Temper Outbursts), for which she and her group are creating web-based resources to help parents develop strategies for caring for children who experience difficult behaviors in response to change. More generally, Dr. Woodcock is interested in understanding how difficulties with change develop in the first place. For example, if a child expresses a preference for routine early on in life, and is accordingly exposed to more routine, one fascinating question is whether such routine is actually detrimental to the child’s ability to deal with change later on. Dr. Woodcock is currently exploring the range of flexibility in routines that children are exposed to, in order to understand how this exposure affects flexibility later in life. Since routine can be helpful for individuals with PWS and their families in some ways, for example in managing food, Dr. Woodcock hopes that exploring this area will help to identify how to strike the right balance between routine and flexibility, and best support individuals with PWS.

Talking to families at PWS conferences has shaped Dr. Woodcock’s research. It was through such conversations that she truly began to appreciate the difficulties associated with extreme temper tantrums in PWS, and the importance of developing therapeutic strategies for dealing with them. She feels that it is a particularly promising time for PWS research, given the current focus on funding of interdisciplinary studies. By virtue of the complex nature of PWS, which affects multiple systems in the body, PWS research requires such interdisciplinary connections, bridging from psychology and neuroscience to genetics and endocrinology.

Outside of work, Dr. Woodcock is an avid traveler. She has lived in Africa, South America, and Asia, including working for Save the Children in Bolivia. She is proud to have taught herself Chinese while living in China during her postdoctoral fellowship, and still likes to practice her language skills by watching Chinese soap operas in Chinese. She also likes running, and was once able to combine her passions for running and travel by completing a marathon along the Great Wall of China.

  • Jeffrey Zigman, MD, PhD

Dr. Jeffrey Zigman recently spoke at the FPWR Research conference in Austin. A two-time recipient of funding from FPWR, Dr. Zigman studies the hormone ghrelin, also known as the “hunger hormone.” Ghrelin levels are higher than normal in individuals with PWS, and Dr. Zigman is trying to understand exactly what role this hormone plays in PWS. We recently sat down with Dr. Zigman for a Skype chat, and learned more about his background, his work on PWS, and his life outside the lab.

Dr. Zigman traces his interest in science back to his childhood. He remembers feeling completely fascinated by a Time Magazine cover story on genetic engineering that he read in 7th grade, around the same time that he did a report for science class on interferons, proteins that the body’s cells produce to defend against viruses. At this point, he had a strong interest in plants, fungi, and science fiction, and was already thinking about a career in scientific research. In college at Cornell University, after a somewhat disappointing experience working with peas in a plant lab, Dr. Zigman spotted a poster about MD/PhD programs, and started thinking about doing basic research in medicine, which would have a direct benefit on humankind. Dr. Zigman was also diagnosed with Type I diabetes while in college, so the opportunity to enroll in an MD/PhD program and study insulin secretion was personally very meaningful to him. He completed his MD/PhD at the University of Chicago, studying G-proteins expressed in the pancreas, under the supervision of Professor Donald Steiner (one of the discoverers of proinsulin, a protein from which insulin is produced). Dr Zigman stayed at U. Chicago for his residency in internal medicine, where he started to appreciate how widespread problems with eating and obesity are, and the importance of the connection between hormones and the brain in understanding hunger and eating. He moved to Beth Israel Deaconess Medical Center in Boston for a fellowship on Endocrinology, Diabetes and Metabolism, where he began to develop his research on the hormone, ghrelin. Since 2006, Dr. Zigman has been on the faculty at University of Texas Southwestern Medical Center, where, as an endocrinologist, he also runs a clinic for patients with thyroid nodules and cancer.

A significant fraction of Dr. Zigman’s research is directed towards understanding how hormones and the brain interact to control feeding. To this end, he has been studying ghrelin for many years. Ghrelin, a hormone primarily released in the stomach, appears to play an important role in telling our brains that we’re hungry. Experiments have shown that ghrelin stimulates appetite and causes animals to start eating, motivates them to seek and obtain food treats, helps them learn how to effectively find food, and enhances the ability of visual cues to stimulate hunger. Given that multiple studies have shown that ghrelin levels are significantly elevated in individuals with PWS, ghrelin may play a role in one of the most difficult aspects of PWS — namely, excessive hunger, or “hyperphagia.”

With previous support from FPWR back in 2007, Dr. Zigman studied mice that were conditioned to favor environments containing special food treats, as opposed to environments with more generic nourishment. The data generated with this initial FPWR-funded study were critical for obtaining support from the National Institute of Health for a more comprehensive research program. With his current FPWR funding, Dr. Zigman is using genetically-engineered mice with the PWS-related SNORD116 gene deleted to serve as a proxy for PWS in humans, and studying the behavior of these mice in various specialized feeding situations. Some mice are additionally being bred to be insensitive to the effects of ghrelin — i.e., they lack ghrelin receptors. Comparison of the mice with and without ghrelin receptors will test the importance of ghrelin in controlling behaviors related to food seeking. Dr. Zigman is also hoping to test the intriguing possibility that ghrelin actually plays a therapeutic role in PWS. Indeed, ghrelin prevents hypoglycemia (i.e., low blood sugar), it’s an anti-depressant, and it can decrease anxiety. Given that hypoglycemia, depression and anxiety are all common issues associated with PWS, perhaps ghrelin levels are elevated to prevent these issues from being even more serious in individuals with PWS. The results of this research may indicate therapies in which a substance akin to ghrelin is given to patients to enhance its positive PWS-related effects. On the other hand, if the most important aspect of ghrelin in PWS is its role in stimulating self-destructive eating habits, potential therapies may include drugs that block the effects of ghrelin. In addition to addressing the *how* of ghrelin and PWS, Dr. Zigman hopes to understand *why* ghrelin levels are elevated in PWS. We look forward to many exciting results on ghrelin from his group.

Given that Dr. Zigman doesn’t treat PWS patients in his clinic, it has been especially meaningful for him to meet PWS families at the two FPWR conferences he has attended. There’s a big difference between measuring the behavior of mice in feeding studies, and hearing about the daily experiences of people living with PWS. Indeed, attending FPWR conferences has truly solidified Dr. Zigman’s passion for studying PWS, and advancing basic research so that effective therapies can be developed.

When he’s not in the lab or treating patients, Dr. Zigman enjoys spending time with his dog, Bubba, and gardening. One of his particular current hobbies is growing fruit trees from the seeds of fruit he eats. You can see that his childhood interest in plants lives on!

  • Rudolph Leibel, MD

Many may remember Dr. Rudolph Leibel’s presentation on stem cells and Prader-Willi Syndrome (PWS) at the FPWR Research Conference in November  2014. Dr. Leibel is the recipient of two recent grants from FPWR, whose goal is to make human neuron cells from patients with PWS. With these special cells, which are just like the ones contained in the brain’s hypothalamus, Dr. Leibel hopes to figure out how PWS works at the molecular and cellular level in the human brain. We recently were fortunate to have the chance to chat with Dr. Leibel about his work and general outlook on PWS.

Dr. Leibel is a pediatrician and pediatric endocrinologist by training.  He received his medical degree from Albert Einstein College of Medicine, was a resident in Boston at both Massachusetts General and Boston Children’s Hospital, and did fellowships at Massachusetts General Hospital and MIT. He has been on the faculty at Harvard, Rockefeller, and Cornell Universities, and a professor at Columbia University since 1997, where he is currently the head of the Division of Molecular Genetics, the co-Director of the Naomi Berrie Diabetes Center, and the Christopher J. Murphy Professor of Diabetes Research. Dr. Leibel has held appointments at numerous hospitals in Boston and New York over the past four decades, and is the recipient of many honors, including being elected to the Institute of Medicine of the National Academy of Sciences.

Dr. Leibel is an international leader in the studies of obesity, the regulation of body weight, and type 2 diabetes. Notably, he played an important role in the discovery of the hormone leptin, which suppresses hunger and makes the body feel full. Although Dr. Leibel treated a few patients with PWS early in his career as a pediatric endocrinologist, his laboratory research has only turned to PWS within the last several years.

At the intersection of molecular biology and neuroscience, Dr. Leibel’s group has recently been able to take human skin cells and convert them into stem cells (the type of cell that differentiate into more specialized cells), which can then be used to generate the type of neurons that are contained in the hypothalamus region of the brain. Dr. Leibel recognized that PWS represents a unique and well-defined scenario leading to obesity, a disorder in which the general role of the hypothalamus in  of obesity and dysfunctional hunger-related behaviors was very likely. Therefore, his group at Columbia has been generating hypothalamic neurons from the skin cells of individuals with PWS deletions of different sizes on chromosome 15, and looking closely at the behavior of such neurons in relation to healthy neurons with no deletions. Intriguingly, the properties of the neurons from a patient with a small “micro-deletion” containing a gene called SNORD116 gene are extremely similar to those generated from PWS patients with more typical, larger deletions.  This result suggests that the deletion of the SNORD116 gene may be critically important for much of the “phenotype” (i.e., observable traits) of PWS — at least regarding excessive hunger. Right now, Dr. Leibel, his postdoc  Liheng Wang and graduate student Lisa Burnett are looking very carefully at how genes are expressed in the hypothalamus neurons they produce, trying to figure out the basic cause at the molecular biological level for the problems associated with PWS. Support from FPWR has been critically important for this project, helping it to get off the ground at the beginning, and providing support for ideas that might have been deemed “risky” but are now clearly paying off.

While it is difficult to pinpoint an exact timescale for when these basic research experiments will translate into specific therapies and treatments for PWS, Dr. Leibel is extremely optimistic for the PWS community. He feels that it is a great time to be studying the neuroscience of the control of body weight, as the tools of neuroscience for understanding how the brain regulates food intake are becoming much more powerful, coupled with novel methods from genetics, optogenetics, and more. Having met PWS families at the FPWR conference, Dr. Leibel also expressed deep respect for how well informed they are on the particulars of the disorder, and for their passion in trying to eliminate the challenges associated with PWS.

Medicine — and even endocrinology — definitely runs in the Leibel family. Both of Dr. Leibel’s daughters are doctors: Natasha is a pediatric endocrinologist, and Alexis is a dermatologist. With such a great role model, perhaps this fact is not too surprising!

  • Yong-hui Jiang, MD, PhD

Many are familiar with Dr. Jiang’s name due to the recent Puzzle Project FPWR. The project funded his study on the screening of small molecules to identify candidate drugs that have the potential to treat PWS at the genetic level. FPWR recently had the opportunity to sit down with Dr. Jiang to learn more about him and his fascinating research.

Dr. Jiang is originally from China, and attended medical school in Shanghai where he became a Pediatric Physician. He found himself working primarily with children with intellectual disability like Down Syndrome, and was interested in finding a way to help his patient population improve their quality of life. He also felt that if he could potentially find a cure for Down syndrome, he would be able to help so many others with different genetic disorders. He left China in the 1990s and came to the United States to begin studying for his PhD and medical resident and fellowship training at Baylor College of Medicine under the mentorship of Arthur Beaudet. It was at Baylor that he was first introduced to Prader-Willi syndrome, and became dedicated to studying the genetic defects in PWS and Angelman’s syndrome.

When asked how FPWR funding has impacted his research, Dr. Jiang described just how important it was in starting his entire project. Without the seed funding from FPWR, he said he never would have been able to put his idea into motion. The research he was able to do with FPWR’s funds provided exciting preliminary data and he has since been awarded a larger grant from the NIH. This grant will allow him to continue this very important and promising research. He reiterated how crucial it is for foundations, like FPWR, to generate funding for scientists and researchers to begin exploratory research, as it can really change the landscape of treatment for disorders like PWS.

The trajectory of Dr. Jiang’s research is very exciting. His first priority is to help his patients with PWS. The key is to find a drug that can do so, but he will also be exploring new mechanisms that can potentially treat symptoms and improve the quality of life for these individuals. Ultimately, he would like to correct the deficit at the genetic level, but on the way, have the ability to develop sub-treatments. Dr. Jiang currently spends 25% of his time working with patients as a Pediatric Geneticist. He finds that working with patients with PWS inspires and motivates him to continue his research. The other 75% of his time he spends working in the lab at Duke University School of Medicine with his talented team of students and postdoctoral fellows.

Outside of the lab, Dr. Jiang is father to two boys; one is in high school and the other is currently in medical school at the University of California at San Francisco. Both his boys play the cello and piano, and together the enjoy classical music, and playing tennis and basketball.

When asked if he had a message for the PWS community, Dr. Jiang said to keep the hope. He has a very strong hope that the research community will be able to help our family members with PWS through treatment and ultimately a cure.

  • Jennifer Miller, MD

To those of us that have children with Prader-WIlli syndrome, Dr. Jennifer Miller is nothing short of a superhero. The hope-spreading, dream-building, cheerleader of parents, is so much more than just that. There is a brilliant mind behind her smiling face and warm heart. We were able to sit down and chat with Dr. Miller recently about endocrinology, Prader-Willi syndrome, and more!

Few people know from an early age exactly what they want to do with their lives, but Dr. Miller was one of the few. She told us that she always knew that she wanted to practice medicine, however, she wasn’t sure about endocrinology. It wasn’t until medical school when she was studying the link between obesity and brain development that her interest was sparked not only in endocrinology, but in Prader-Willi syndrome. Dr. Miller first earned both a B.S and M.S in chemistry from Emory University in just 4 years, graduating with high honors. She then graduated from the University of Florida with her M.D, and later pursued her M.S in Clinical Investigation. To date, Dr. Miller has been at the helm of several research projects with a focus on evaluating the effects of early-onset obesity (i.e. obesity occurring before age 4) on the developing brain. She currently sits on the Scientific Advisory Board for the Foundation for Prader-Willi Research, and is hosting an exciting clinical trial at the University of Florida on the effects of Intranasal Oxytocin on individuals with PWS.

Dr. Miller says that she is grateful to FPWR and the One SMALL Step initiative for allowing her lab to continue to do important research and to learn more about Prader-Willi syndrome. Furthering an understanding of the facets of PWS will lead to more clinical trials, and hopefully treatments that will help our kids.

In chatting about PWS and the evolution of the research since she became involved, Dr. Miller shared with me how exciting it has been to offer tangible hope to families over the past 4 years. When I asked if she had a message for the PWS community, Dr. Miller said, “this is an exciting time for researchers and families. There are so many new possibilities for treatments and so much research going on and the future is looking bright for our kids”.

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  • James Hougland, Ph.D.

Outside of the lab, Dr. James Hougland has been happily married for over 10 years and is a father to two small children. He enjoys cooking, and reading scientific and alternative history. At work, he is a multi-award winning biochemist at Syracuse University and recipient of a 2013 BIG Grant through The Foundation for Prader-Willi Research. FPWR funded his study on ghrelin O-acyltransferase (GOAT), an enzyme that modifies ghrelin.

We reached out to Dr. Hougland to find out more about how he chose a career in science and his perspective on PWS research.  We are excited to highlight him in our Researcher Spotlight. Read on to find out more about the man behind the project!

Dr. Hougland has always been interested in the science and research fields, and wanted to understand the rules that control how the world functions. He describes himself as “someone who’s not just curious about how things work, but someone who can’t bear *not* knowing how things work”.  Currently at Syracuse University, one of his areas of research is studying the enzyme GOAT, which plays a role in converting the hunger hormone ghrelin from its inactive to its active state. He became interested in Prader-Willi Syndrome when he learned of the possible role of ghrelin in PWS hyperphagia. His hope is that by developing new molecules that affect the enzyme that activates ghrelin, we will be able to better understand how these pathways function and possibly open the door to therapies targeted at ghrelin activity.

Dr. Hougland says the funding that he received through FPWR and the One SMALL Step initiative has allowed his lab to make significant progress in the last year in studying GOAT, which is a rather challenging enzyme to work with. He is hopeful for the future of his research for PWS. He says that his research is currently aimed at developing inhibitors of GOAT in order to decrease ghrelin levels in the bloodstream and ghrelin related hunger signaling. Once developed, the inhibitors can be used to better understand how ghrelin levels affect appetite in PWS, and could possibly lay the groundwork for a potential therapy.

This year FPWR launched and funded its first ever Young Researcher Initiative Award. This award is supporting an undergraduate student summer internship in the Hougland lab at Syracuse University. The student, Ariana Garagozzo, is not only a young scientist but also has a sibling with Prader-Willi Syndrome. For more information, click here. Dr. Hougland deeply values getting to know individuals and families of the PWS community, saying that it helps him to understand the impact that his work has beyond academics. Importantly, he tries to reinforce that impact to his students as well.

When asked if he has a message for the PWS community, Dr. Hougland says, “I’m still a relative newcomer to PWS research, but I’m seeing a large community of researchers from a variety of fields (medicine, biology, chemistry, etc.) come together to study and understand PWS. The most important step in addressing scientific challenges is to assemble the right people asking the right questions, and my sense is that we’re well on our way towards that goal.”


  • Dr. Tony Goldstone


Tony Goldstone attended medical school at Cambridge and Oxford Universities in the UK, and trained in general medicine, adult endocrinology and diabetes at the Hammersmith, St. Bartholomew’s and Royal
London Hospitals in London. He obtained his Ph.D. from Imperial College London on the hypothalamic control of feeding and metabolism.

He has researched and published widely on hormonal control of appetite, neuroendocrine, hypothalamic and metabolic abnormalities in obesity and Prader-Willi syndrome, particularly investigating the causes of hyperphagia, through pre-clinical, clinical, post-mortem, genetic, interventional, fat and brain imaging studies.

He is currently a Clinical Senior Lecturer at Imperial College London, and a Consultant Endocrinologist at Imperial College Healthcare NHS Trust with specialist adult and paediatric clinics for patients with Prader-Willi syndrome, as well as in-patient and emergency care of patients within Endocrinology, Diabetes and Acute Medicine.