Jul 31, 2011
@9:58 PM

Vision for future genetic research

After college, I spent 13 years in training from 1996-2009, first with an M.Phil. in Genetics, then an M.D. and Ph.D., followed by residencies in child, adolescent and adult psychiatry. Since July 2009, I have been working independently in Utah, and I have led the discovery of the first human disease involving a defect in the N-terminal acetylation of proteins. We are currently calling this new disease Ogden Syndrome, in honor of where the first family resides. I have also led efforts to use exome sequencing in the complex disorder of attention deficit hyperactivity disorder (ADHD), including how to handle unrelated findings arising from such studies. I have also collected many other DNA samples from multiple pedigrees affected with certain disorders, including rare unknown diseases, Tourette Syndrome, ADHD, obsessive compulsive disorder (OCD), mental retardation, autism and schizophrenia. I have amassed detailed phenotyping records on these research subjects, and I expect to conduct genetics research on these samples for many years to come. In addition, I continue to see patients and research subjects for ~1 week per month in Utah.

Sydney Brenner famously stated the following: “What I’m advocating is: go the other way. Let’s go from bedside to bench. We don’t have to look for a model organism anymore, because we are the model organisms.” I agree with Dr. Brenner 100%. Instead of compartmentalizing research and medicine, the two should be integrated so that physicians who are most familiar with human “phenotypes,” can inform the other arms of science. This is precisely the reason that I spent five years in rigorous clinical training in psychiatry at numerous hospitals and institutions, including at Columbia, NYS Psychiatric Institute, Rockland State Children’s Psychiatric Center, ACS, and Bellevue Hospital. This included substantial work in two of the largest and busiest psychiatric emergency rooms in the country. All of this was to prepare me to study human genetic variation in medicine in general, and with a focus on neuropsychiatric disorders.

I have always intended for my training to prepare me for a truly translational career in human genetics and disease. Prior to residency training, I obtained research experience in chemistry, molecular biology, structural biology, and genetics. During residency training, I conducted research in clinical trials. I plan to help understand over the course of my entire research career how human genetic variation contributes to the manifestation of certain rare and common diseases, particularly in the neuropsychiatric space, using human as “the model organism”. We are entering an exciting period in which we will discover and explain many idiopathic diseases, and I expect that we will soon discover many more mutations involved in autism, schizophrenia, Tourette Syndrome, bipolar disorder, ADHD and OCD. However, proving causality will be the major issue, and therefore having access to research subjects and tissues derived from them will be critically important, hence the pressing need for clinician-scientists to lead these efforts.

One way to make headway in the genetics of many complex disorders is by focusing on large pedigrees living in the same geographic location, where one can study the penetrance and segregation of variants in a similar environmental background and free of population stratification concerns, particularly given the possible penetrance of only ~40-60 percent for mutations in some disorders. Utah is the single best place in America to do this, so I collect research subjects at the Utah Foundation for Biomedical Research and see patients at the company Clinical Methods. I have simultaneously focused on rare Mendelian disorders due to being more tractable currently. I realize that the genetics of complex neuropsychiatric disorders like autism and schizophrenia is much more difficult, which is why I have set aside hopefully the next 30 years to work on this problem. My training has also left me with no illusions or naivety concerning the challenges in drug development, but I believe I can help develop with many other scientists over the next 30 years therapies targeted toward genetic subtypes of certain psychiatric disorders. Some researchers have already started toward this goal in the area of Fragile X. Just as the war on cancer is beginning to bear fruit in targeted therapies ~30 years into the “war”, I expect we can make substantial progress in the realm of neuropsychiatric disorders over the next 30 years.

My single best skill as a physician-scientist is seeing across disciplines and being able to set up productive collaborations to discover and understand new and existing diseases, as illustrated by the Ogden Syndrome story. Going forward, I plan to elaborate with colleagues the mechanistic basis of Ogden Syndrome in terms of N-terminal acetylation.  I have also collected multiple other rare, “idiopathic” syndromes and I want to pursue their genetic basis and pathophysiology in collaboration with many other scientists. I also plan to pursue the genetics with DNA samples that I have collected in complex neuropsychiatric disorders. It is too early to conclude what portion of neuropsychiatric disorders will end up being readily explained by single changes in the genome, and whether they will be point mutations, deletions, duplications, or other forms of variation consistent with an oligogenic explanation. But, recent research has suggested that 5% of autism can be explained by various large copy number variants, so it is likely that some additional portion of the heritability will be explained by smaller mutations just not currently detected. Such discoveries will set the stage for translational research and eventually drug development. The genetic basis of cystic fibrosis was reported in the late 1980’s, and it appears likely that a drug targeted toward the genetic defect in a subset of patients will be approved by the FDA this year or next. It can currently take 15-30 years to translate genetic discoveries into medical treatments, and I hope to contribute to and perhaps accelerate such efforts going forward.

–Gholson Lyon, MD, PhD

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