The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

Abstract

In January 2020, a novel pathogen exploded into the global biome. Within weeks of its discovery, scientists designed a vaccine that targeted the virus’s spike protein. Within a year, safety and efficacy were established and more than 50 million people had received their first dose. The new vaccine embodied an idealized, linear version of medical progress: 1) identify an illness; 2) determine its cause; 3) characterize the mechanism; 4) develop a treatment; and 5) prevent, mitigate, or cure the illness. Across medicine, there are numerous examples that were designed in this fashion: ACE (angiotensin-converting enzyme) inhibitors for hypertension, HAART (highly active antiretroviral therapy) for HIV, trastuzumab for HER2+ breast cancer. And then there’s psychiatry. By and large, the field remains stuck between steps 1 and 2. We have barely scratched the surface of psychiatric pathophysiology. Within this space, schizophrenia epitomizes the complexity of psychiatric illness. It was first described as dementia praecox by Emil Kraepelin in 1893, and little progress was made in understanding its pathophysiology until the 1970s. Twenty years after the discovery of chlorpromazine, researchers learned that the medication antagonizes dopamine receptors. Subsequent work linked dopamine hyperactivity to positive symptoms, such as hallucinations and delusions. The dopamine hypothesis dominated the field for decades and informed an entire generation of antipsychotic medications—and then a second (1Moghaddam B. Krystal J.H. Capturing the angel in “angel dust”: Twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans.Schizophr Bull. 2012; 38: 942-949Crossref PubMed Scopus (181) Google Scholar). But this model painted an incomplete picture (e.g., by not accounting for negative or cognitive symptoms). Others sought to understand one of schizophrenia’s most vexing properties: while it was clearly heritable, nobody could figure out how; the tools simply did not exist. A crucial insight eventually emerged from a lost and seemingly unrelated moment in history. In the 1960s, British geneticist Patricia Jacobs was conducting pioneering research on how genetic markers were distributed in families (2St Clair D. Blackwood D. Muir W. Carothers A. Walker M. Spowart G. et al.Association within a family of a balanced autosomal translocation with major mental illness.Lancet. 1990; 336: 13-16Abstract PubMed Scopus (606) Google Scholar). Her team decided to study a group of boys at a Scottish youth detention center known as a borstal. The borstals were infamously brutal and abusive environments. Many of the children had experienced lives of violence and neglect; once there, they often exhibited signs of severe mental illness. This seemed like a prime population to look for genetic abnormalities. At the time, the only way to study genetics was by looking at the gross appearance of chromosomes under a light microscope. Remarkably, even with these limited tools, the team identified a child who had a balanced translocation between chromosomes 1 and 11; they then found the same translocation in several members of his family. While this was notable at the time, 20 years later a separate team circled back and discovered something even more interesting: not only did the boy have a severe psychiatric illness, but so did many of the family members who shared his translocation. This part of the genome appeared important to the development of mental illness. But due to technological limitations it was impossible to study in greater detail. They were at an impasse. By the late 1990s, other research was beginning to challenge the established dopaminergic dogma. Several groups, including John Krystal’s team at Yale, became interested in the role of the NMDA receptor (1Moghaddam B. Krystal J.H. Capturing the angel in “angel dust”: Twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans.Schizophr Bull. 2012; 38: 942-949Crossref PubMed Scopus (181) Google Scholar). The work was based in part on observations that ketamine and phencyclidine, both NMDA antagonists, mimicked some of schizophrenia’s clinical features. They hypothesized that disruption of glutamatergic signaling might be central to its pathophysiology. Meanwhile, a separate story was emerging from David Lewis’s team in Pittsburgh. Postmortem studies of patients with schizophrenia revealed differences in inhibitory GABAergic (gamma-aminobutyric acidergic) interneurons. These cells play a crucial role in cognition, and their dysfunction could help explain what the dopamine hypothesis could not. Eventually it became apparent that the GABA and glutamate hypotheses could be two sides of the same coin: dysregulation of GABA inhibition might be either the cause of or a compensatory response to glutamate dysfunction (3Glausier J.R. Lewis D.A. GABA and schizophrenia: Where we stand and where we need to go.Schizophr Res. 2017; 181: 2-3Crossref PubMed Scopus (30) Google Scholar). Things were getting complicated. By 2001, the Human Genome Project had been completed and geneticists had a range of new tools. As other complex illnesses (like Crohn’s disease) were being linked to specific gene variants, researchers were finally able to circle back to the boy from the borstal. They identified a gene that was altered in both the patient and his affected family members: DISC1 (4Blackwood D.H. Fordyce A. Walker M.T. St Clair D.M. Porteous D.J. Muir W.J. Schizophrenia and affective disorders—Cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: Clinical and P300 findings in a family.Am J Hum Genet. 2001; 69: 428-433Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar). It appeared that they had found a key to unlocking the secrets of schizophrenia—a singular gene that, when disrupted, drastically increases the risk of the disease. Sadly, reality proved far more complicated. DISC1 is important. Subsequent research has demonstrated its role in many neuronal processes, from microtubule transport and cytoskeleton construction to neurogenesis and dendritic spine formation. Disruption of DISC1 does lead to complex psychiatric disorders. The problem is that it only affects a tiny percentage of individuals with schizophrenia. Which is to say: it may be a cause of schizophrenia—but it is clearly not the cause. Then, in 2013, an unexpected story shook the field. One morning, journalist Susannah Cahalan woke up in a psychiatric ward with no idea of how she had gotten there. She eventually learned that she had become psychotic and then catatonic. The severity of her symptoms, the precipitousness of their onset, and the rapidity of her decline baffled her physicians. Then, after thousands of dollars’ worth of diagnostic testing, neurologist Souhel Najjar turned to a low-tech solution: he asked Ms. Cahalan to draw a clock. The test suggested hemispatial neglect, which, alongside other neurological findings, ultimately led him to the newly described diagnosis of anti-NMDA receptor encephalitis. Cahalan’s antibodies were binding to NMDA receptors, much as ketamine and phencyclidine do, causing a syndrome that looked a lot like schizophrenia (5Kayser M.S. Dalmau J. Anti-NMDA receptor encephalitis in psychiatry.Curr Psychiatry Rev. 2011; 7: 189-193Crossref PubMed Scopus (115) Google Scholar). This staggering presentation raised the question: how many similar cases were being missed? After an initial flurry of research, it became clear that the story was much like that of DISC1: while anti-NMDA receptor encephalitis can cause symptoms resembling schizophrenia, it is simply not that common. This series of events—discovery of a possible cause, excitement over its potential, and inevitable disappointment over its limited scope—has played out again and again throughout the history of schizophrenia research. Another high-profile example arose in 2016 from a massive genome-wide association study. Among 108 loci associated with schizophrenia, researchers found a striking relationship between schizophrenia and genes associated with complement C4 (6Sekar A. Bialas A.R. de Rivera H. Davis A. Hammond T.R. Kamitaki N. et al.Schizophrenia risk from complex variation of complement component 4.Nature. 2016; 530: 177-183Crossref PubMed Scopus (1367) Google Scholar). This was an especially compelling finding because of the role complement plays in targeting synapses for destruction during periods of pruning. Excessive pruning could lead to reduced cortical volume, dysfunction at the glutamatergic synapse, and myriad other pathological changes known to be associated with schizophrenia. And yet, as compelling as the finding was, it seems to explain only a sliver of cases. Moreover, this still represents an unusually strong genetic association. Other recent studies have demonstrated that multiple common genetic variants, each of which has a very small effect size on its own, contribute collectively and in large numbers to increase the overall risk of schizophrenia in a given subject (7Purcell S.M. Wray N.R. Stone J.L. Visscher P.M. O’Donovan M.C. et al.International Schizophrenia ConsortiumCommon polygenic variation contributes to risk of schizophrenia and bipolar disorder.Nature. 2009; 460: 748-752Crossref PubMed Scopus (3430) Google Scholar). An even more recent paper has highlighted the impact of ultrarare variants (8Singh T. Poterba T. Curtis D. Akil H. Al Eissa M. Barchas J.D. et al.Rare coding variants in ten genes confer substantial risk for schizophrenia.Nature. 2022; 604: 509-516Crossref PubMed Scopus (71) Google Scholar). Schizophrenia, it appears, is a polygenic illness typically associated with thousands of common variants and, occasionally, by a few rare variants with larger effect sizes. At this point it is abundantly clear that schizophrenia is not a single entity, but a heterogeneous collection of conditions that cause overlapping clinical features. Still: might these conditions share some overlapping pathophysiology? In fact, this seems to be the case: most causal factors of schizophrenia appear to disrupt either the structure (e.g., DISC1 or C4) or function (e.g., anti-NMDA receptor antibodies or phencyclidine) of the glutamatergic synapse. As Coyle et al. (9Coyle J.T. Ruzicka W.B. Balu D.T. Fifty years of research on schizophrenia: The ascendance of the glutamatergic synapse.Am J Psychiatry. 2020; 177: 1119-1128Crossref PubMed Scopus (20) Google Scholar) note in a recent review: “convergent pathology by strikingly different mechanisms reinforces the hypothesis that the loss of cortico-limbic glutamatergic synapses is the fundamental pathogenic feature in schizophrenia.” And for a lot of people diagnosed with schizophrenia, this is how it probably all fits together: Loss of functionality at glutamatergic synapses results in precipitous cognitive decline, often with decreased cortical gray matter volume. It also impairs the feedback inhibition mechanism of cortical GABAergic circuits, causing disinhibition of subcortical dopaminergic neurons (thereby resulting in many positive symptoms of schizophrenia). So, where do we go from here? Sadly, an emerging truth is that schizophrenia cannot be “cured” —at least not today. And yet there is reason for hope. The reality is that we already have tools and techniques that are enormously effective at helping people with schizophrenia: early detection and intervention, mobile care teams, wraparound postcrisis services, integrative approaches that focus on recovery and inclusion, and attention to social determinants of health (10Insel T. Healing: Our Path from Mental Illness to Mental Health. Penguin, New York2022Google Scholar). These things work today, and we would be wise to invest more resources into them. In the meantime, research will go on. Precision approaches will continue to identify discrete (and potentially treatable) entities within the broader syndrome. Lest we be too down on ourselves, we are not alone in the field of medicine. The purported scientific ideal of a linear path from discovery to treatment is the exception rather than the rule. Science is messy. It took decades to gain traction treating “cancer”—we should expect and embrace the same journey for “schizophrenia.” Clinical Commentaries are produced in collaboration with the National Neuroscience Curriculum Initiative (NNCI). David A. Ross, in his dual roles as Executive Director of the NNCI and as Education Editor of Biological Psychiatry, manages the development of these commentaries but plays no role in the decision to publish each commentary. The NNCI is funded in part by the Deeda Blair Research Initiative Fund for Disorders of the Brain through support to the Foundation for the National Institutes of Health. DAR receives support from the Alberta Health Services Chair in Mental Health Research. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of Defense or the United States Government. SLW owns shares in the following biomedical companies: Abbott Laboratories, Amgen, Merck & Co., Johnson & Johnson, Eli Lilly & Co., Pfizer, Edwards Lifesciences Corp., and Illumina Inc.