I have been asked by several people what I thought of the recent NY Times article “Schziophrenia As Misstep by Giant Gene” by Nicholas Wade (Science Times, Tuesday, April 18, 2006).The gene focused on is neuregulin-1 (NRG1) and how a variant form (polymorphism) may be involved in the expression of the disorder. NRG1 is one of many genes thought to be potentially linked to the expression of schizophrenia. The article emphasized the difficulties in sorting out cause and effect in this research, i.e., are the observed alterations a function of the illness itself or causal (and I would add, or both). Drs. Daniel Wienberger and Law presented research on Type 4 proteins (whose function is unknown but thought to be involved with neuronal migration-a key process centered on in certain neurodevelopmental models of schizzophrenia). and the gene variant which codes for the latter. These researchers found that people who inherited two versions of this variant segmment (one from each parent), produced 50% more of neuregulin’s Type 4 proteins. The resarch is suggestive of, but does not prove, a causal role of the NRG1 gene in schizophrenia The location of NRG1 is on 8p12-there is evidence for an altered expression in the dorsal lateral prefrontal cortex in schizophrenia.. The following are the leading candidate genes being researched today.

Sullivan and colleagues (2006-”Textbook of Schizophrenia” edited by Jeffrey A.Lieberman, T. Scott Stroup and Diana O. Perkins for American Psychiatric Publishing, Inc.) pointed out that the “pathogenesis of schizophrenia is unknown, and no compelling biological markers of sufficient sensitivity and specificity exist” (p. 40). However, they noted that current research on the molecular genetics of schizophrenia nominates several genes of potential importance in the etiology of schizophrenia: neuregulin 1 (NRG1), dystrobrevin binding protein 1 (DTNBP1), G72 and G30, regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH), disrupted in schizophrenia 1 and 2 (DISC1 and DISC2), serotonin 2a receptor (HTR2 A), and dopamine 3 receptor (DRD3). The evidence for etiological risk is strong for genes NRG1 (although a recent study published in Psychological Medicine, 2005, 35, 1599-1610, “Neurgulin 1 (NRG1) and schizophrenia: analysis of a US family sample and the evidence in the balance,” failed to find an association between NRG1 and schizophrenia) and DTNBP1, intermediate for genes RGS4, G72/G30/DAO, HTR24, and DRD3 and weak for genes COMT and PRODH. It is important to bear in mind that one should be cautious in the etiologic interpretation of the results of linkage and association studies-the classical molecular genetic study designs in humans-because they only yield statistical support for candidate genes for schizophrenia. These studies alone cannot prove the etiological significance of a particular gene and it is likely that some of these candidate genes will prove to be false positives. However, it would be a monumental advance if even one of these genes prove to be of etiological significance.

The field of neurogenetic research in schizophrenia is replete with initial positive leads which upon further investigation turn out to be false positives. On can think of the Neuregulin 1 (NRG1) gene as an example of this. NRG1 is known to be involved in glutamatergic function and has been found to be associated with schizophrenia in some samples. Recently, Duan et al (2005-”Neureggulin 1 (NRG1) and schizophrenia: analysis of a US family sample and the evidence in the balance” Psychological Medicine, 35, 1599-1610) demonstrated no evidence of association at a single-marker or a haplotypic level. They concluded that the failure to find an association between NRG1 and schizophrenia might reflect different linkage disequilibrium (LD) patterns found in different populations, disease allelic heterogeneity, clinical heterogeneity of schizophrenia, or inadequate statistical power deriving from moderate sample size. if NRG1 is a ‘true’ gene for schizophrenia, it accounts for a small fraction of the illness in most populations. Sullivan and colleagues (2006) believe that variants in NRG1 (which is thought to be an important regulator of glial cells and myelination as well as a broad range of neuroreceptors including nicotinic acetylcholinergic and NMDA glutamtergic receptors), despite the modest linkage evidence, may confer susceptibility to schizophrenia.

van Os and Sham (2003-”Gene-environment correlation and interaction in schizophrenia’ in “The Epidemiology of Schizophrenia” edited by R. Murray, P. Jones, E. Susser, J. van Os & M. Cannon and published by Cambridge University Press) emphasized gene-environment relationships as etiological factors in the schizophrenias. They deliniated various forms of gene-environment relationships: gene-environment correlation (a gene may increase the likelihood that a person becomes exposed to various environmental risk factors); gene-environmental synergy (exposure to both, rather than neither or either one alone, may result in disease expression); gene-environment additive interaction (the person must have a certain type of vulnerability conferred either by genetic or environmental factors); and gene-environment multiplicative interaction (disease expression is dependent upon genes and environmental factors in multiple

stages).

There exists conflicting evidence for previously held biological markers (endophenotypes) for an underlying genetic diathesis such as abnormalities in smooth pursuit eye muscle tracking (also observed in bipolar patients, an example of the non-specificity of neuroscience findings in schizophrenia). Researchers demonstrated a functional basis to this deficit in recent-onset schizophrenic patients by showing improvement through attentional training (get ref). as Colin Ross pointed out “...a deficit in performance of smooth pursuit eye movement tasks, usually assumed to be a biological marker of the genetic predisposition to schizophrenia, is significantly related to physical and emotional abuse in childhood (Irwin, Green, and Marsh, 1999)” (p. 35). qEEG studies with MZ twins (Gruzelier, Galderisi & Strik 2002)) demonstrated that abnormalities pointed to non-genetic sources of variance. MacCabe et al (2005-”Saccadic distractbility is elevated in schizophrenia patients, but not in their unaffected relatives” Psychological Medicine 35: 1727-1736) demonstrated that saccadic distractibility is strongly associated with disease status but not with genetic loading for schizophrenia. Therefore saccadic distractibility is not useful as an endophenotypic marker in schizophrenia. A team of investigators at the Institute of Psychiatry in London (Wykes et al 2002) demonstrated that patients with schizophrenia who had received a psychological treatment, cognitive remediation therapy (CRT), had significantly increased brain activation in regions associated with working memory, i.e., frontocortical areas.Perhaps, ourpsychoanalytic genome project would be to study the transgenerational transmission of traumatic experience that has been foreclosed. Davoine (1990) referred to the work of Francoise Dolto, a French child psychoanalyst, who “compared disturbed children to sleepwalkers trespassing on the forbidden dreams of their parents...walking without knowing, right through the ‘no-entry’ signals of their parents and demonstrating publicly the poorly kept secrets (p. 53). I believe that children walk along the perimeters of their parents nightmares, and represent them in their symptoms.

Sapolsky (2005) presents us with research which demonstrate the importance of the environment in gene expression. Genes, stretches of DNA, do not code for behaviors, hallucinations or delusions. They code for proteins and some of these proteins certainly are related to how we think, feel and act. Neurotransmitters, neurohormones, receptors, enzymes, intracellular messesngers, etc., are all made of proteins. However, it is rare that such molecules cause a particular behavior. Rather, they produce tendencies to react to particular environments in particular ways. Sapolsky uses the subject of anxiety to illustrate this: neurotransmitters and genes do not make you anxious-they make you more sensitive to anxiety-provoking situations and may make it more difficult to detect safety signals within those environments. Genetic status, in many of the psychiatric disorders, is not all that predictive in and of itself. The biological factors coded for by genes do not typically determine behavior, rather they influence responsiveness to environmental influences. In our field we are often dealing with genetic vulnerabilities and biases, not genetic inevitabilities.

It is important to note that there are long stretches of DNA, perhaps 95% of our DNA, which do not get transcribed. Some of this noncoding DNA-regulatory elements, promoters, repressors, responsive elements- is used as an instructional manual for how and when to activate genes. Often, it is the environment which regulates this genetic activity. On another level of complexity, the environments which we generate as individuals and as a cultural group, can change the pattern of gene activity in oneself and within other individuals. Genes can be viewed as convvenient tools which are used by environmental factors to influence behaviors. In addition, there is a significant degree of variability in DNA sequences among individuals and it is the noncoding regions of DNA which contain the greater share of this variability. Therefore, evolution can productively be viewed as a process of natural selection for different genetic sensitivities and reactions to environmental influences.

Sapolsky (2005), in considering the lessons from the above research studies, concluded:

“Obviously, beware of simple explanations; it is rare that nature is parsimonious... Sometimes genetics is about inevitability-if you have the gene for Huntington’s disease...there’s a 100 percent chance you’re going to have this awful neurological disease by middle age. But in far more realms than people usually expect, genes are about vulnerabilities and potentials, rather than about destiny.

And out of that comes a social imperative-genes do indeed seem to play a role in some of our less desirable behaviors. But what knowledge about those genes keeps teaching us is that we have that much more of a responsibility to create environments that interact benignly with those genes” (p.56).

Walter Freeman, Pofessor at the University of California at Berkeley prominent neuroscientist, has authored many volumes on brain science, including “Neurodynamics: An Exploration in Mesoscopic Brain Dynamics.” In his relatively recent volume “How Brains Make Up Their Minds” published by Columbia University Press, Freeman (2000) explores the difficult question of free will and intentionality from a neuroscience perspective. I believe this has great relevance for the human condition and human behavior in general, but for our understanding of mental illness in particular. Freeman asks the question: Who is really in charge of yourself, your genes, brain or you? He points out that beyond the doctrines of genetic (nature) or environmental (nurture) determinism, which lie at the heart of the nature-nurture debate, is the peron’s own contribution to choices, decisions, circumstances, etc. Freeman is committed to a point of view in which the power to choose is an essential and unalienable property of human beings. Freeman (2000) noted:

“What is at issue is the nature of self-determinism. The problem boils down to the questions of how and in what sense brains, with their cells, the neurons, can create actions and thoughts, which we experience as our minds and ourselves, and whether and how our experiences can change or influence our brains and their neurons. What does it mean to say that one causes the other? “ (p. 3).

Freeman goes to great lengths to explain the neural processes through which goals emerge within brains and find expression in goal-directed actions.

Merzenich and deCharms (1996) pointed out that functional activity and plasticity are inseparable. Sounding more like neurophilosophers than the basic neuroscience researchers that they are, noted:

“We believe that mind is the product of an environment expressed in the nervous system and manifested by it through actions; it is a circular and relational interaction among an incoming world, an experiential context, and outgoing activity. To a large extent we choose what we will experience, then we choose the details that we will pay attention to, then we choose how we will react based on our expectations, plans, and feelings, and then we choose what we will do as a result. This element of choice and the relational nature of awareness in general have almost never been considered in neurophysiological experiments. We realize now that experience coupled with attention leads to physical change in the structure and future functioning of the nervous system. This leaves us with a clear physiological fact, a fact that is really just a mechanistic confirmation of what we already know experimentally: moment by moment we choose and sculpt how our ever-changing minds will work, we choose who we will be the next moment in a very real sense, and these choices are left embossed in physical form on our material selves” (p.76).

Schizophrenia & Epigenetic Processes

Changeux (2002) noted that the word ‘epigenetic’ is composed of two Greek roots: epi, which means ‘on’ or ‘upon’ and ‘genesis’ which means ‘birth.’ He used the term to underscore the impact of learning and the environment upon gene function. Epigenetics has been referred to as a “second, largely secret code” (Kramer 2005). In 2003, Europe organized a “human epigenome project” and in 2004, the Center for Epigenetics of Common Human Disease was established at Johns Hopkins University. Kramer (2005) has defined epigenetics as “the study of stable alterations in gene expression by nongenetic mechanisms [I would say processes] resulting in stable alterations in phenotype” (p. 25). In a deep sense, epigenetics is a form of biological or environmental programming in which the mother transmits to the offspring a form of forecasting of likely environmental conditions to be faced by the latter.

Arturas Petronis (2004) defined epigenetics: “By definition, epigenetics refers to regulation of gene expressions that are controlled by heritable but potentially reversible changes in DNA methylation and/or chromatin structure” (p.175-in “Schizophrenia, neurodevelopment, and epigenetics” in “Neurodevelopment and Schizophrenia” edited by Matcheri Keshavan, James Kennedy & Robin Murray in 2004 for Cambridge University Press).

A large number of genes exhibit an inverse correlation between the degree of methylation and gene expression, which lends support to an increasing body of experimental evidence suggesting that epigenetic modification is closely involved in the regulation of the expression of genes. One of the processes of epigenetic regulation of genes is related to methylation of the binding sites of transcription factors, leading to a change in the affinity of these factors for the regulatory sequences of these specific genes. This seems to be linked to another type of epigenetic regulation, that is, various types of histone modification. DNA is wrapped around histone complexes to form nucleosomes-depending on DNA and histone modifications, chromatin can be transcriptionally competent or not. Transcriptionally competent chromatin is normally enriched with acetylated histones, while transcriptionally silent chromatin is deacetylated. The interaction of DNA methylation and histone acetylation shows that the two types of epigenetic regulation act in concert. Epigenetic factors play a role in DNA mutagenesis and repair as well as in DNA recombination and possibly replication. Epigenetic patterns are transmitted similarly to DNA sequences, from maternal chromatids to daughter chromatids during mitotic divisions, and transmission of this epigenetic status is termed the “epigenetic inheritance system.” Unlike DNA sequenses, which exhibit almost complete interclonal fidelity, epigentics usually exhibits only partial stability. The partial stability of epigenetic modification is termed “epigenetic metastability.” There is evidence that some epigenetic signals escape erasure during maturation of gametes and, importantly, casn be transmitted across generation (inducible defences against predatory

threat, as in the transgenerational transmission of trauma?).

Eva Jablonka and Marion Lamb (2005) have detailed the many different forms of epigenetic inheritance systems-EIS (see their “Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life” published by MIT Press). Jablonka and Lamb described the following EIS’s:self-sustaining feedback loops-memories of gene activity; cellular structural inheritance-architectural memories, e.g., prions in Creutzfeldt-Jakob disease, i.e., ‘mad cow’s disease’; chromatin-marking systems-chromosomal memories (chromatin is the DNA plus RNA, proteins, including histones, etc.-the ‘stuff’ of chromosomes)-methylated DNA significantly influences gene transcription and are also a part of the heredity system that transfers epigenetic information from mother cells to daughter cells; and RNA interference (RNAi) which leads to the stable and cell heritable silencing of specific genes (depending on small RNA molecules known as siRNAs). Besides the pathways of genetic and epigenetic inheritance, Jablonka and Lamb (2005) delineate two more inheritance systems: behavioral and symbolic. The latter two being significant for psychosocial scientists in their attempts to understand mental illnesses. Epigenetic research, I believe, will become much more significant in the future as applied to psychiatric disorders. The pharmaceutical companies are already researching how their psychopharmacological agents impact on the epigenetics of psychiatric illnesses. However, since the role of the social environment looms much larger within psychiatric epigenetics, psychosocial interventions, including most importantly, psychotherapy, will be increasingly recognized as ameliorative.

Two key aspects of epigenetic modification of the genome make epigentics very relevant to schizophrenia. First, epigenetic modifications of DNA and chromatin orchestrates the activities of the genome, including regulation of gene expression. Epigenetic metastability is the second key aspect of relevance to schizophrenia. Epigenetic regulation of genes undergoes significant reorganization during development and aging as well as under the influence of extracellular factors (e.g., the hormonal status of the organism-cortisol expression during times of threat?) or environmental factors. Epigenetic regulation represents the dynamic feature of a gene and genome, whereas most of the DNA sequences do not alter during the life of the individual. Time of onset of schizophrenia may correlate with major hormonal (in particular cortisol hormonal expression) rearrangements in the individual. Epigenetic status of the gene is one of the targets of hormone action. Various hormones have a significant impact on gene expression, and this is secured by changing chromatin conformation and/or local patterns of gene methylation. A disease process may be initiated by hormone (e.g., cortisol)-mediated epigenetic changes in critical genes.

Wahlberg et al (1997-Gene-environment interaction in vulnerability to schizophrenia: findings from the Finnish Adoptive Family Study of Schizophrenia. American Journal of Psychiatry 154:355-362) found a significant association between communication deviance in adoptive parents and thought disorder in those children thought to be at genetic high risk for schizophrenia, having had a biological mother with a diagnosis of schizophrenia, but not in low risk adoptees. They believed this is consistent with genetic control of sensitivity to the environment. Importantly, there was no difference in the presence of communication deviance in the adoptive parents of high risk versus low risk adoptees, thus suggesting that the adoptees at high risk did not have a special impact of increasing the communication deviance in their adoptive parents. Tienari and colleagues (2002) research has demonstrated that healthy environments are neuroprotective and unhealthy rearing environments are neurodisorganizing, particularly in more vulnerable individuals. This genetic diathesis need not be seen apart from environmental influence. Research has consistently demonstrated the noxious effects of prenatal stress on the developing fetal neuroaxis. This potential source of variance, as well as any history of substance abuse in the biological mother during pregnancy, would need to be controlled before one could validly posit a ‘genetic’ diathesis.Tienari et al (2002) demonstrated that both genetics and environment add to MR (morbid risk). These investigators made the very important observation:

“Genotype-environment interaction (G X E) can be defined as a genetic control of sensitivity to environmental factors, or environmental control of gene expression. Thus, some genotypes are more likely than others to develop disease in the event of exposure to certain environmental factors. In the case of genotype-environment interaction, diseases will tend to cluster in families not because of a direct genetic effect, but because relatives are more vulnerable to the risk-increasing effect of a prevalent environmental risk factor. It is possible that neither the genetic susceptibility nor the risk factor can influence the disease risk by itself, but risk is increased when both are present. These and other examples are important in that they illustrate that a genotype associated with a disorder may not indicate any genetic role in the causal pathway to the disorder but may identify who is or is not susceptible to an environmental causal factors.” (p.36).

Jones (2002) emphasized that we must depart from a neuroreductionism which attributes schizophrenia to “bad genes.” In its place should be a model that recognizes that “...different combinations of genes have different effects, and, again, may interact with events, environmental or behavioural, that are themselves trivial but, in combination with the particular genetic diathesis lead towards bad outcomes” (p.329).

Leon Eisenberg (2004) in his article “Social psychiatry and the human genome: contextualizing heritability” (British Journal of Psychiatry, 184: 101-103), pointed out that genes alone are not the secret code or blueprint for life. He noted:

“The [dogma] of one gene/one protein, a useful fable for its time has been exploded; alternative splicing permits multiple proteins from a single gene. Thirty thousand plus genes code for 100,000 plus proteins; epigenetic post-translational modifications create the potential for a million different proteins that must interact to produce a viable human being. The assembly of these components reflects not merely the code but biological and social pulls and pushes at work during its fabrication. Men and women, in all our diversity, emerge from these intricate and unpredictable interactions. Nature and nurture stand in reciprocity, not opposition. Offspring inherit, along with their parents’ genes, their parents, their peers and the places [sociocultural contexts] they

inhabit.”

Eisenberg concluded that “genes set the boundaries of the possible; environments parse out the actual.”

I shall conclude this section on genetics with observations by Richard Lewontin (2000), Professor at Harvard University, taken from his volume “The Triple Helix: Gene, Organism, and Environment” (published by Harvard University Press):

“The reigning mode of explanation at present is genetic. Reinforced by the observation that some human disorders result from mutation of clearly defined genes, nearly all human variation is now ascribed to genetic differences. From the undoubted fact that gene mutations like the Tay-Sachs mutation or chromosomal abnormalities like the extra chromosome causing Down syndrome are the sources of pathological variation, human geneticists have assumed that heart disease, diabetes, breast cancer, and bipolar syndrome must also be genetic variants. The search for genetic variation is a major preoccupation of medical research...The trouble with the general scheme of explanation contained in the metaphor of development is that it is bad biology. If we had the complete DNA sequence of an organism and unlimited computational power, we could not compute the organism, because the organism does not compute itself from its genes....There exists, and has existed for a long time, a large body of evidence that demonstrates that the ontogeny of an organism is the consequence of a unique interaction between the genes it carries, the temporal sequence of external environments through which it passes during its life, and random events of molecular interactions within individual cells. It is these interactions that must be incorporated into any proper

account of how an organism is formed “(pp. 17-18).

Lewontin concluded:

“The organism is determined neither by its genes nor by its environment nor even by the interaction between them, but bears a significant mark of random processes. The organism does not compute itself from the information in its genes nor even from the information in the genes and the sequence of environments. The metaphor of computation is just a trendy form of Descartes’s metaphor of the machine. Like any metaphor, it catches some aspect of the truth but leads us astray if we take it too seriously” (p. 38).

In regard to genes and mental disorder in generals, I would summarize that the current thinking by geneticists is as follows:

Schizophrenia, or mental illness in general, may be thought to arise frompolygenic factors, i.e., many genes, of low to moderate effect, which are in a dose-response non-linear relationship with multiple hgh risk environmental factors. Neurogenetic reductionism in psychiatry, is what it has always been, a costly and erroneous short-cut to the comprehensive understanding and treatment of complex mental disorders which arise from complex non-liinear interactions between genes (including epigenetic processes), brain, mind (which includes multiple factors at the level of

the individual and family), as well as the sociocultural surround (a complex framework which includes vertical and horizontal dimensions, especially involving the transgenerational transmission of trauma, or what Finnish psychiatrist-psychoanalyst Martti Siiral calls the transfer of burden which is waiting for the chance of dialogical encounter, perhaps in what psychoannalysts have called the transference).

In conclusion, for those interested in current thinking on the role of genes in mental disorders, and in the human condition generally, I would highly recommend Sir Michael Rutter’s “Genes and Behavior: Nature-Nurture Interplay Explained” published in 2006 by Blackwell Publishing.

Brian Koehler PhD
Postdoctoral Program
New York University
80 East 11 Street #339
New York NY 10003
brian_koehler@psychoanalysis.net
212.533.5687