January 1, 2008
Mission Statement
Our laboratory is committed to discovery of the fundamental causes of major psychiatric illnesses. It is our belief that development of effective treatments will be greatly facilitated by a rational understanding of the molecular mechanisms that cause these illnesses. We pursue this mission with a combination of basic research and technology development.
Basic Research
Informatic Psychiatry - Towards a New Paradigm for a New Era in Psychiatric Research
For the past 11 years, our focus has been on major psychiatric disorders such as obsessive-compulsive disorder, Tourette syndrome, body dysmorphic disorder, bipolar disorder and schizophrenia. Our approach differs from the traditional approach that attempts to identify molecular defects responsible for illness by comparing a large number of subjects having a particular diagnosis with an otherwise similar group of healthy controls. A major problem is that studies conducted with this approach have proven to be extremely difficult to reproduce and therefore generate little confidence in their results. Our analysis suggests that for the above illnesses, a large and heterogeneous set of molecular-level defects can lead to the same diagnosis. This heterogeneity may be responsible for the notorious difficulty of replicating traditional studies of gene-associations and treatment efficacy.
To avoid the complications resulting from the molecular heterogeneity underlying diagnostic categories, we carry out long-term, in-depth studies of smaller numbers of individuals in which we collect comprehensive general medical histories and long-term behavioral histories. The detailed historical information is then combined with comprehensive genetic and other molecular-level information to develop molecular-level hypotheses for the illness of each individual. These hypotheses can be tested experimentally, either through their predictions for treatment or by in vitro molecular studies. In this approach, we do not make the assumption that different individuals with the same diagnosis have the same molecular defects.
In our approach, the focus is not only on subjects with illness but also on their healthy, close relatives, since we believe that any valid theory of an individual’s illness will also explain the absence of illness in healthy relatives. Our approach is made feasible, in part, by the recent development of revolutionary molecular methods that provide comprehensive information on DNA sequences, levels of gene expression, and many other aspects of cell biology. It is also being made feasible by our own development (see below) of new, internet-based methods to capture and define the phenotypic manifestations of psychiatric illness much more easily and precisely than has been possible in the past. A core feature of our approach is the combination of massive amounts of genetic and other molecular information with massive amounts of behavioral information to facilitate correlation of microgenetic features (e.g. specific polymorphisms) with microbehavioral features. We refer to this approach as “Informatic Psychiatry” and we see it as a new paradigm for personalized psychiatric research in the rapidly emerging era of personalized medicine.
Technology Development
An Internet Interface for Psychoinformatics
In 2007, there was a dramatic illustration of the possibilities for personalized research and medicine as a result of the publication of two accurately and fully sequenced human genomes. Current predictions suggest that reductions of the cost of full-genome sequencing (to ~$10,000) will make it readily available as a routine procedure within several years. In contrast to the revolutionary methods for genetic analysis, methods for characterizing the manifestations of the genome (i.e. the “phenotype” or collectively the “phenome”) are in the proverbial “dark ages.” Nowhere is this more apparent than with psychiatric disorders, where the primary manifestations of genetic abnormalities reside in the details of day-to-day behavior and inner mentational experience.
Available methods for psychiatric evaluation are fundamentally problematic, since they depend on the subjective judgments of psychiatrists and psychologists. Moreover, they require manual collection of data by highly trained individuals in personal interviews, making them expensive and cumbersome. Development of objective methods to capture and describe mathematically the enormous variety of human behavior and mentation is a major, unsolved problem and is an important agenda in this laboratory. An aspect of this agenda is the development of internet-based techniques for the automatic collection and analysis of data from remotely located subjects. We expect that microbehavioral information can be captured not only with automatic interview algorithms but also with web-based sensor technology, leading to behavioral histories with unprecedented accuracy, objectivity, and detail. Moreover, the information density and objectivity of microbehavioral histories promises to facilitate valid studies of drug efficacy without the use of placebos or blinds.
We believe that a facile internet interface for automatic collection of historical information combined with modern pattern recognition technology for automatic analysis will initiate a new discipline which we refer to as "Psychoinformatics." The combination of Psychoinformatics with the revolutionary developments in Bioinformatics and Cell Biology will implement our vision of an "Informatic Psychiatry" that is worthy of the postgenomics era of psychiatric research.
The Cellbot: A Robotic Toolbox for Stem Cell Research
A breakthrough in the last year promises to facilitate the routine production of pluripotent stem cells from adult skin cells. The availability of stem cells from any individual promises to facilitate in vitro production of neurons and other brain cells that are genetically identical to those of the skin cell donor. This will make it possible to study in vitro the functional consequences of the genetic defects found in individuals with psychiatric illness. These patient-specific in vitro studies will be facilitated by the Cellbot, which is a robotic system for the automatic manipulation and molecular analysis of cultured stem cells that is being developed in this laboratory. In this NIH-funded project, we have recently developed novel algorithms that promise to eliminate the need for human observers in automatic systems for microscopy and manipulation of cells.
The technology development in this laboratory is driven entirely by its ability to contribute to our basic research studies.