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DISC1 2010: 20 Years of DISC1 Celebrated In Edinburgh

5 September 2010. The first schizophrenia conference devoted to the universe of a single gene, DISC1 2010 kicked off this weekend in Edinburgh, Scotland. Certainly there wasn't a disrupted in schizophrenia 1 (DISC1), per se, in 1990, but the gene was there on the long arm of chromosome 1, waiting for some intrepid Scottish pioneers, led by David St Clair, Douglas Blackwood, and Walter Muir, to come along and point out its hiding place. St Clair and colleagues noted that major mental illness could be traced to a balanced translocation—a swapping of genomic material—between chromosomes 1 and 11 in an extended Scottish family.

At a heavily jetlagged Friday night gathering of some 90 aficionados from around the globe, conference co-organizer David Porteous welcomed all with great pride to the city of Edinburgh, "A Capital City…A City of Learning and Culture." After describing the many cultural opportunities at hand, Porteous extolled the virtues of Scottish sweets and the ability to get beer already at 11:00 a.m. in the conference center bar, and warned of the dangers of the local soft drinks. But he also promised "a fantastic diet of science," and turned the floor over to fellow organizer Blackwood for a brief tour of the history of DISC1 (which perhaps is really code for Discovered In Scotland).

Looking back
Blackwood began with an interesting side story that moves the original date back another 20 years. He noted that the DISC1 kindred first came to the attention of Patricia Jacobs at the University of Edinburgh in the late 1960s. Jacobs, who, incidentally, in 1965 had been the first person to link a chromosomal abnormality (chromosome 47, XXY) with a disorder (Klinefelter syndrome), was not investigating schizophrenia, but rather aggressive behavior. She and her colleagues first published the chromosome 1 abnormality in that regard in 1970 (Jacobs et al., 1970).

Regarding the extended DISC1 kindred that he and his colleagues subsequently characterized, Blackwood opined that while the cohort was certainly special, it was in other ways typical. Specifically, he meant that the incidence and range of other psychopathologies in the family—from mood disorders to anxiety and alcoholism—does not look noticeably different from other kindreds identified by having several members with schizophrenia.

In addition to the historical perspective, Blackwood did mention some relevant new data built on his work with the P300 EEG signal as an intermediate phenotype. He and his colleagues had shown that carriers of the 1:11 translocation, regardless of psychiatric diagnosis (or lack thereof), have abnormalities in p300 measures, and researchers at the Institute of Psychiatry in London have recently found that a DISC1 risk single nucleotide polymorphism (SNP) alters P300 in a separate group of patients with psychotic disorders.

Blackwood concluded his discussion of DISC1 with some observations on the fact that DISC1 has not been a "hit" in genomewide association studies (GWASs) (see SRF review of GWASs). He suggested that "it's the context that matters," for example, haplotypes and SNP-SNP or gene-gene interactions.

Looking forward
In an appropriate bookend to Blackwood's survey of accomplishment, Tom Insel, director of the U.S. National Institute of Mental Health, then took a dispassionate look at "the road ahead." But he paused first to take note of the P300 data, which he thought represented the right approach—the intermediate or endophenotype approach to evaluating schizophrenia risk genes.

Insel's main thesis was that the field is just coming to grips with how difficult psychiatric disorders will be to explain and better treat, and he organized his talk around three assertions: that 1) a gene is not a target; 2) a target is not a drug; and 3) an antipsychotic drug is not the answer. Insel offered up an immeasurably simpler disorder—sickle cell anemia—as an instructive example for the first. Although the eponymous cellular pathology was identified by James Herrick in 1910 (Herrick’s syndrome), and the molecular basis by Linus Pauling in 1949, a real target first emerged nearly a century after Herrick's paper. In 2008, researchers zeroed in on a completely different molecule, one that regulates the expression of hemoglobin genes that are expressed only before adulthood. This repressor now represents the first real target for sickle cell anemia, but it also comes up against the reality of Insel's second assertion—that a target is not a drug. He noted that only one in 25 targets actually makes it through the minefield that is drug development.

Finally, Insel drew on the example of type 1 diabetes to illustrate the fact that successful treatment of psychosis since the 1950s has not changed the morbidity or mortality of schizophrenia. What may provide real benefits is to view schizophrenia as a developmental syndrome, and this is where type 1 diabetes is instructive. Over time, research in this field has established a prodrome preceding the moment when insulin-producing β cells are depleted to the point that patients require insulin. The focus of research is to protect the β cells during this prodrome. While we can only dream of having a single cell type to protect in schizophrenia, any hope for drugs that go beyond antipsychotics will depend on establishing the key molecular prodromal events in the disorder, argued Insel.

Where does DISC1 fit into this story? As a postscript, Insel projected out another 20 years, with the hope that DISC1, its interactome, and other genes like it could help define a number of different neurodevelopmental disorders that we now lump together under one rubric. Thus, in the next few days of the DISC1 2010 meeting, we hope to learn whether DISC1 is likely to become a Rosetta Stone, leading us to the messages of how to understand and treat schizophrenia and other major mental disorders.—Hakon Heimer.

Reference:
Jacobs PA, Brunton M, Freackiewicz A, Newton M, Cook PJL, Robson EB. (1970) Studies on a family with three cytogenetic markers. Ann Hum Genet, 33, 325.

 
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