Paradigms of the Mind

BETHESDA, Md.--My first impression of the National Institute of Mental Health (NIMH) was formed long prior to my arrival there this summer. When I was a kid, "The Secret of NIMH" was one of my favorite movies. It was the kind of film that my brother, sister and I rented so many times from the video store that we might as well have bought it. Actually if I had followed the advice of Nicodemus and his wise band of rats, I would have run away from NIMH, not toward it. Literal lab rats, Nicodemus and company, were the tortured subjects of the cold, calculating scientists of NIMH. My siblings and I applauded their valiant escape from NIMH's fearsome clutches.

So why did I choose NIMH as the place of my summer internship? I was admittedly relieved when I found out that I wouldn't be responsible for any animal experimentation in the lab. But more importantly, I was and still am grappling with questions about the mental processes and their origins. Primarily, I've been struggling with finding the paradigm I'm most comfortable with using to examine human consciousness. Cognitive science is a burgeoning field that employs analytical frameworks running the gamut from computer algorithms to psychological models to biochemical pathways. Meanwhile, these latest tools for thinking about thinking fit into an even broader tradition of introspection. Where today clinical definitions landmark the boundaries of normal and abnormal cognition, the psychiatric case studies of the past were more likely to be described in a Shakespeare play or Dostoevsky novel than in the pages of a medical text.

Finding my role as a neuro- or cogneuro- scientist, I'm trying to sort out not only what it means to think, but from what vantage point I can investigate thinking in the most clear-sighted--or should I say clear-minded--way. This is not an effort very different from that of Nicodemus and his heroic troops. The rats of NIMH caution us that it is sometimes in the search for what makes us greatest--in this case, civilization and wisdom--that we become more estranged rather than closer to what makes us so.

This summer at NIMH, I've faced some tough issues about the direction in which neuroscience and psychiatry are headed. Once the art of the medical world, psychiatry is now the focus of the latest pharmaceutical technology and biomolecular manipulation. The laboratory where I've been working takes a genetic approach to analysis of bipolar affective disorder (BPAD, otherwise known as manic depression) and schizophrenia, each of which is estimated to affect 1 percent of the population worldwide. Deep within the bowels of NIMH, our effort to climb to the seat of the mind had been relegated to a lab in the windowless basement--we spend our days isolating and sequencing DNA. We look for changes in the base pair sequences, called nucleotide polymorphisms, that might characterize people suffering from these disorders. Weeks might go into the process of finding a G (guanine) replaced by a C (cytosine) on a schizophrenia susceptibility gene.

Labelling genetic polymorphisms is an interesting and very controversial way of investigating psychiatric illness. There is little question that people's mental states are the product of both genetic and environmental influences; nature and nurture co-choreograph our intellectual steps and missteps. Still, it often seems superficial and reductionist to explain complex mental machinations with a chromosome number and base substitution. How can we possibly acknowledge the flair of the human thought process by merely pinpointing a genetic locus?

I haven't found a simple answer to this question, but I have come upon some satisfaction in the discovery that the field of neurogenetics is not as pat as I had feared. BPAD and schizophrenia are both marked by multifactorial genetic inheritance; they are not the results of basic Mendelian transmission. This means that there is a whole host of genes that is involved in the development of either disorder. What lends neurogenetics its literally mind-boggling puzzles are questions addressing possible interactions of these genes: Do the additive effects of a number of genes create the phenotypic spectrum of the trait (for example, in BPAD from mild depression to rapid cycling BPAD)? Must a critical threshold be reached for manifestation of the illness? Even if a person has all of the genes that code for a disorder might its expression be prevented or mitigated by protector genes (These genes manufacture factors that can switch off the genes that are doing the damage)? Genes of this type are already known to be important in the expression of BPAD, though how big a role they play is anyone's guess. Dwarves born in to families where BPAD is common rarely develop the disease, despite the challenges they face in life that could easily act as environmental triggers. It seems that the dwarfism gene confers resistance upon carriers to the BPAD genes that they might also have.

Inside the neurogeneticists' community there is more argument than consensus over the genes involved in mental health. Diagnosis of psychiatric illness is notoriously subjective and genetic heterogeneity is the rule, not the exception, even when diagnosis is more certain. In order to trace inheritance patterns neuroscientists focus on a genetic isolate population whose members suffer from a disorder with unusually high frequency. My lab's investigation of BPAD used a genetic isolate from the Old Order Amish in Lancaster County, Penn. Not only were we able to find several families with expression rates of BPAD as high as 20 percent, but the sociological profile of our population has also helped the integrity of the study. The Amish keep flawless family trees that make drawing up pedigrees much easier for geneticists. Furthermore, the stereotypical behavior of BPAD easily stands out in their highly structured society.

While these findings haven't yet convinced me that I want to devote my life's work to neurogenetics, they have modified the picture of the cold, calculating scientist at work at NIMH. Statistical uncertainty in genetic studies, disagreement over diagnostic guidelines and the sociology of genetics isolates show that there is humanist method to the scientific madness of neurogenetics. Hollywood producers: I think that "The Secret of NIMH" is due for a sequel.

Dalia L. Rotstein '03, a Crimson editor, lives in Pforzheimer House.