On Monday, March 17, two Indiana University mental health researchers, Dr. John I. Nurnberger and Dr. Alexander B. Niculescu III, addressed the weekly PredictER meeting at the IU Center for Bioethics in a talk entitled: “Genome-Wide Association Studies: What Have We Learned So Far". Dr. Nurnberger is the current director of the Institute of Psychiatric Research at the IU School of Medicine and Dr. Niculescu is Assistant Professor of Psychiatry and the Director of the Laboratory of Neurophenomics. Niculescu, Nurnberger and others recently published a widely discussed [see Steve Mitchell, MSNBC, 25 Feb. 2008] blood biomarkers for mood disorders study [PMID 18301394 - PDF].
Current Challenges in Understanding and Treating Mental Health Disorders
Dr. Nurnberger (who chaired the first portion of the lecture) began the talk by outlining the prevalence of various neuropsychiatric disorders, focusing especially on Bipolar disorder. Dr. Nurnberger's discussion was supplemented by an explanation from Dr. Niculescu of some of the shortcomings that past attempts to understand the genetic links to depressive/Bipolar disorders have had. According to Dr. Niculescu, “Until recently, the lack of concerted integration between the two approaches [has]… constituted a missed opportunity to accelerate our understanding of this complex and heterogeneous group of disorders”. Simply put, mood disorders involve many, many genes, which may be present in various combinations in any one of us, and interact in ways that defy easy classification. While it is clear that individuals with certain psychiatric disorders may have certain combination more often, we are far from understanding precisely which genes are responsible for which portions of the disorders.
Dr. Niculescu then detailed two main “arms” of his research; the first involves an innovative response to the problem of how to create a sophisticated working picture of the genomics involved in mental illness. Using a technique called Convergent Functional Genomics (CFG), Dr. Niculescu's team brings data from three sources together - animal model gene expression data, human genetic linkage/association data, and finally human tissue (postmortem brain, blood) data.
The advantages of bringing these there sources of information together are manifold. Dr. Niculescu’s team has been able to cross-validate findings from other research studies. This has helped his team to “extract meaning from large datasets" and to prioritize "candidate genes, pathways and mechanisms for subsequent targeted, hypothesis-driven research”. Furthermore, as Dr. Niculescu indicates, this convergent functional genomics approach may help to deliver on one of the most exciting and elusive goals of genetic research in the area of mental health: a blood test that could identify blood biomarkers of an illness.
“PhenoChipping” and the Move Towards More Individualized Mental Health Care
As part of working towards this goal, Dr. Niculescu’s research team is implementing another innovative approach – the use of PhenoChipping. In layterms, a gene is thought to be like a “blueprint” for how something biological is built; a phenotype is the way that thing is actually built and lives, which may diverge from the plan, or may change over time according to its environment. “PhenoChipping”, thus, refers to the process of collecting mental health data from subjects using a massive inventory of cognitive and affective tools. Researchers are hoping to combine this “in vivo” data with advanced genomic data to better understand what complex interaction of genes, environments, stress, and other factors participate in these serious and highly complex neuropsychiatric disorders.
Dr. Niculescu and his team see their research as moving towards the development and implementation of more tailored, personalized treatments in psychiatry. In this more personalized medicine the patient's unique profile is the target of therapeutic interventions. Dr. Niculescu states: "We hope our work will contribute to better diagnostics, early intervention and prevention efforts, and more efficacious treatments, with reduced side-effects".
Some Ethical Questions:
This research is a rich playing field for bioethics with its intersection of illness, consent, duress, technology, and research whose implications (and even direction ) can barely be anticipated from where we stand. Some questions to consider are:
What are the ethical issues to be considered when conducting research on populations of people that are ill, and ill in a way that affects judgment?
What does consent to mental illness research mean in the absence of a cure?
What if we were able to develop a blood test that help predictive capacity for determining if someone was at risk of developing a mood disorder? What would individuals want to know, and under what circumstances?
In what ways would the ethics of this predictive, diagnostic power mimic existing models in the ethics of disclosure of illness? How, for example, would it differ from existing ethical frameworks for disclosing HIV status, terminal illness, and other conditions?
What does participation in long-term mental health genomic studies mean for participants? Can participants “withdraw” from research, and if so, what happens to their data?
– Noah Zanville
[PredictER Blog welcomes this first contribution from Noah Zanville. Noah is nursing student in the accelerated track at the Indiana University School of Nursing. He serves as a member of IU School of Nursing's Leadership Council and is a key figure working with the local chapter of National Student Nurses Association. He is currently preparing to accept a position as a Research Assistant doing applied bioethics research around end of life issues in ICU settings through the Charles Warren Fairbanks Center for Medical Ethics.
Noah earned his bachelor's in Philosophy from the University of Oregon, and is a Licensed Massage Therapist with an emphasis in Lymphedema Management, Medical Massage in acute-care settings and energy work. Noah also worked as a free-lance medical illustrator for a time.]
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