Welcome to FarSighted

For decades, geneticists and molecular biologists have promised that they would soon uncover the keys to understanding human biology. For these scientists the Human Genome Project was an exalted campaign to provide all of the raw genetic information necessary for a molecular understanding of human disease and behavior. It was thought, that after the project’s completion, it would be a simple task to identify the genes responsible for depression, breast cancer, and big noses. The HGP was to be the crowning achievement of a 400 year narrative of biological reductionism.

The first hint of trouble came when it was discovered that the human genome contained only 20-30,000 genes. Less than a third of the original estimate of 100,000 genes, this low number of genes demolished the One Gene:One Protein theory. The practical consequence of this is that it was proven that most genes were needed to perform different functions at different times. This finding proved prophetic as it was discovered that most diseases and traits are not mendelian but rather complex traits, determined by interactions of multiple genes (in fact some claim that there is no souch thing as a non-complex trait). For obvious reasons it is much harder to uncover the genetic components of a complex trait than a mendelian one. More recently the ‘story’ has been further complicated by the discovery that gene regulation and non-protein coding genes play much bigger parts in gene fuction than previously thought.
Increasingly, it seems that integrating discoveries from nascent fields such as epigenetics and functional genomics will require a fundamental recasting of our approach to biology. Since the time of Descartes, western science has been dominated by the impulse to break problems down into “by dividing them into smaller, simpler, and thus more tractable units (1). In biology this has manifested itself as a search for the individual factors responsible for a higher order phenomena. While this philosophy has been wildly successful until now, it is inadequate for describing the complex interactions between genes, epigenetic systems, and the medley of proteins and RNAs in the cellular environment, that combine to respond to every environmental input into the cell. A new holistic, systems-based approach will be neccessary to fully understand the implications of epigenetics and functional genomics.

Far from being the final frontier of molecular biology, genetics has proven to be a launching point for a new age of exploration. In this blog we will chronicle this stage in the quest for understanding of molecular biology. We will keep tabs on progress from the incipient stages of research into epigenetics and the development of next-generation genetic technologies. We will also pay close attention to how these developments affect the future of medicine and psychiatry.

Farsighted should be navigated by selecting the “Page” of interest and following the links from there.

Disclaimer: much of the writing in this blog is speculative. I am not a recognized expert on any of it. Furthermore, as suggested by the title of the blog, my interest in these areas is somewhat far-sighted ie, my presentation of the present may be inaccurate.

Down Syndrome Mouse

Looks like the Down Syndrome Mouse is really starting to pay off

Two papers in the July 6, 2006, Neuron, published by Cell Press, report evidence that surprisingly simple genetic abnormalities in the machinery of critical neuronal growth-regulating molecules can kill neurons in Down’s syndrome, Alzheimer’s disease, and other neurodegenerative disorders. The researchers said their basic findings could aid progress toward treatment for the cognitive deficits in these disorders.

n humans, Down’s syndrome is caused by a trisomy–an abnormal three copies of chromosome 21. Such trisomy causes an increased “dosage” of genes on that chromosome, and a central mystery of Down’s syndrome is how such an overdose of particular genes leads to such abnormalities as mental retardation.

In their papers, Salehi and colleagues and Tessarollo and colleagues studied mice genetically engineered to mimic the trisomy seen in human Down’s syndrome. Their aim was to discover the machinery by which this trisomy ultimately causes the death of neurons that are important for cognitive function.

Salehi et al. find that an increase in the expression of only one gene, for amyloid precursor protein (APP), disrupts transport of the neurotrophin “nerve growth factor” (NGF). APP is also a central molecule in the pathology of Alzheimer’s disease.

The Dorsey et al. paper describes how restoring the normal cellular levels of a Trk receptor for the neurotrophin “brain-derived neurotrophin factor” (BDNF) rescues neuronal death in another mouse model of Down’s syndrome.

Salehi et al. found that the NGF transport disruption leads to the degeneration of “basal forebrain cholinergic neurons” (BFCNs) important for cognitive function. This deterioration of BFCNs is similar to that seen in Alzheimer’s disease and is caused by abnormal APP function. Since in people with Down’s syndrome, the APP gene resides on the trisomic chromosome, Salehi and colleagues reasoned that an overdose of APP might also play a role in neuronal degeneration in Down’s syndrome and thereby contribute to cognitive deficits in both Down’s syndrome and Alzheimer’s disease.

Obstacles to Gene Therapy

• Short-lived nature of gene therapy – Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.
• Immune response – Anytime a foreign object is introduced into human tissues, the immune system is designed to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a potential risk. Furthermore, the immune system’s enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in patients.
• Problems with viral vectors – Viruses, while the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient –toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
• Multigene disorders – Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer’s disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy.

Gene-targeting

Whereas transgenesis involves ‘positive’ or ‘additive’ gene transfer, Gene-targeting procedures are used to disable or ‘knock out’ a candidate gene (23). A construct is designed that has two regions of homology to the target gene, flanking a selectable marker. These markers are bacterial genes that offer resistance to neomycin, hygromycin, or puromycin, which will disrupt the segments of DNA that are either essential for transcription and/or translation. Recombination between the flanking sequences of homology in the targeting construct and the genomic locus replaces the host gene sequence with the selectable marker. [Again the mouse is used as an example animal] The cells that have the selectable marker integrated into their genome are chosen by means of molecular screening techniques prior to being microinjected into blastocysts and implanted into pseudopregnant mice. The heterozygous mice that are produced are mated together to generate homozygous knockout mice, which lack a functional copy of the candidate gene. Gene-targeting is sometimes used to generate mice with a mutation in, rather than inactivation of, the candidate gene. In these cases, a construct identical to the endogenous DNA (other than the desired mutation) is made.

Compared to transgenesis, gene-targeting is an elegant system because it can control both the number of copies as well as the point of insertion. More accurate phenotype modeling is achieved via the absence of insertional mutagenic effects, the complete elimination of the endogenous candidate gene, and its expression in specific cells and tissues. Furthermore, in cases where gene-targeting is used for expressing mutated genes, the mutated gene will be expressed under the same transcriptional patterns as the gene of interest. The experimental advantages of gene-targeting are offset to some degree by its relative labor-intensiveness; transgenesis can yield a stable mouse-line in a matter of months, whereas a gene-targeting line can take years to come to fruition.

Like transgenesis, significant refinement of techniques are necessary before gene-targeting procedures can be applied to therapeutic use in humans.

Transgenesis

Transgenesis is a technology used to introduce a gene of interest into an animal model for study. [This article will use the mouse as an example animal] Cloned genetic material called a construct is created, for insertion into the mouse embryo. Expression is restricted to a specific tissue by fusing the candidate gene to a cardiac-specific promoter in the transgenic construct. To produce a stable genetic modification, the construct is injected into the pronucleus of a one-cell embryo. The embryo is then implanted into a pseudopregnant female mouse. Mouse pups are genotyped and the transgenic mice, the founders, are mated to produce the stable line (6). Transgenesis is typically used to induce overexpression of transcriptional levels of the candidate gene. However, neither the copy number nor the point of insertion can be controlled, and both the transgene and the native gene are expressed. Consequently, it is necessary for the transgene expression to be dominant over its homologue in order to produce a phenotype. Furthermore, DNA insertion can result in mutagenic effects in the flanking DNA, complicating any resultant phenotype. Hence, several independent founders are generated to check the levels and sites of transgene expression and compare the phenotypes. Transgenesis is typically used to investigate endogenous protein function and signal transduction pathways.

If transgenesis sounds a lot like gene therapy – thats because it is. The process I described is very similar to what could one day be used for germline gene therapy. Because of the expertise gained from generating transgenic mice, germline gene therapy may be more easily achieved than somatic gene therapy. However, the technology is still very crude at this point, and needs to be refined before therapeutic use in humans is possible.

Current Status

After more than twenty years of gene therapy, there are still no publicly available gene therapy regimens. After early success in (in vitro) experiments, application to humans has proved to be surprisingly problematic. The clinical trials began in 1990, but have been plagued by technical problems ever since. In fact, serious health complications and deaths in a number of recent clinical trials has raised calls for increased regulatory scrutiny over future clinical trails. For example, in January 2003, the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells after two children in a French gene therapy trial developed a type of Leukemia.

GENE THERAPY TIMELINE

• 1980 – Richard Mulligan, an M.I.T. researcher, shows that genetically engineered mouse-leukemia retroviruses were effective messengers for carrying human genes into mouse DNA.
• 1989 – Dr. French Anderson, Eli Gilboa and Dr. Michael Blaese win approval from an National Institutes of Health (NIH) advisory panel for a test that would transfer bacterial genes into immune cells of terminal cancer patients. The trial paves the way for dozens of gene-therapy efforts.
• 1990 – Dr. French Anderson and Michael Blaese perform the world’s first officially approved gene therapy by manipulating human genes. The patient is a 4 year-old girl named Ashanti DeSilva. She inherited a defective gene from both parents and suffered from ADA (adenosine deaminase) deficiency. The scientists introduce millions of Ashanthi’s own white blood cells into her bloodstream that were extracted from Ashanthi’s blood and genetically engineered to contain a corrected (“therapeutic”) copy of the adenosine deaminase gene. The scientists hope these cells will restore Ashanthi’s immune function by producing a normal version of the defective enzyme. The treatment appears to have been a success.
• 1999 – The sudden death of Jesse Gelsinger, a patient undergoing experimental treatment for a rare liver disorder at the University of Pennsylvania, raises scores of questions about various aspects of gene therapy. Penn officials say Gelsinger’s immune system had a severe inflammatory reaction that caused multiple organs in his body to fail.
• 1999– NIH discovers that researchers did not report 6 gene therapy patient deaths. Public backlash intensifies
• 2000 – Reporters uncover hundreds of unreported cases of “adverse effects” for gene therapy trail.
• 2001 – First germline gene transfer – 30 children born as a result of ooplasmic transfer. Ooplasmic transfer (also referred to as ooplasmic or cytoplasmic transplantation) is a fertility procedure used by women who cannot conceive because of defects in their ooplasm – their eggs’ cytoplasm. The procedure is performed by inserting healthy ooplasm from donor eggs into the eggs with defective ooplasm. By inserting healthy ooplasm from the donor eggs into the mother’s defective eggs, a small amount of mitochondrial DNA is transferred into the egg. This is considered germline gene transfer because the mitochondrial DNA of these children, and of their offspring, will always be from the donating mother.
• 2002 – Two children who were cured of “bubble baby syndrome” (X-SCID), were discovered to have developed a leukemia-type disease.
• 2003 – FDA temporarily halts gene therapy trials using retroviral vectors in blood stem cells. This is the first restriction of government regulation of gene therapy trails since they were allowed in 1989.

Dr. Frankenstein’s Mouse

This is a little out of date, but Dr. Irving Weissman plans to create the first chimera in the United States. He wants to genetically engineer a mouse with human neurons. The resulting transgenic mouse would be useful for testing drugs for schizophrenia, ALS, parkinson’s, alzheimers and other neurological diseases, as each neuron would be completely human. As of now, the plan is to kill the mice if their brain structure or behavior deviates from normal mouse behavior.

I wonder if this will become a big story in the general media.

Schizophrenia Mouse

Scientists at John Hopkins have announced the creation of a new researchers admitted that “Rodent models of schizophrenia have significant limitations. The neuronal circuits affected in people are more complex than the analogous circuits in rodents. In particular, the relative size of the prefrontal cortex that is involved in the cognitive deficits is much smaller in rodents than in primates. Some of the cognitive symptoms such as hallucinations or delusions are impossible to address.”

Personally, I can’t get too excited because (as you may already know) I am a big believer in the developmental nature of schizophrenia. But, as always, I wish them luck as I am happy to be proven wrong.

Post-psychiatry

The triumph of the reductionism of the Greeks is a pyrrhic victory: We have succeeded in reducing all of ordinary physical behavior to a simple, correct Theory of Everything only to discover that it has revealed exactly nothing about many things of great importance. R.B. Laughlin and D. Pines

As stated earlier, contemporary psychiatry seeks fulfillment of its reductionist and essentialist goals through genetics. However the first era of genetics, the identification of individual (and groups of) genes and their individual roles, is nearly over. Its reign has yielded minimal results for biological psychiatry. On the horizon is Functional Genomics, the study of how genes interact with each other and their environment, over time. Functional genomics not only identifies the biological task of a given gene, but it identifies how and in what conditions it is activated. Furthermore, functional genomics recognizes that genes do different things under different conditions, and consequently understands that genetic destinies are at least co-authored by environment.
Ironically, functional genomics is an intrinsically non-essentialist, non-reductionist science. After decades of reductionism “medical research is entering the era of synthesis” it is time to explore “interactions between subsets of possible genetic and environmental agents as causations in particular contexts indexed by time and space.” Functional genomics is interested in how genes interact over time, in response to cellular conditions. This approach inherently acknowledges exogenous environment and culture, opening the door for acknowledgement of the role of factors such as psychogenic ‘triggers’. Additionally, functional genomics defies the traditional diagnostic framework. Rather than further delineating mental illnesses into distinct diseases with unique molecular mechanisms, functional genomic approaches will blur and even disintegrate distinctions between diseases with related disease processes. Illness will be understood as being on a spectrum of human conditions rather than grouped into distinct categories that must be explained by common origins. Rather than attempting to prioritize contributing factors to make a global model for mental illness, models will necessarily be personalized. Already these shifts in understanding are beginning to permeate our culture: in the last two years, three popular science books have been published highlighting the role of mental illness in creativity, entrepreneurship, and human evolution.
Undermining and eliminating the essentialist and reductionist tendencies of psychiatry will have two effects. First, it will lead to the personalization of medical care. The disintegration of diagnostic classifications will lead to treatment strategies fitted to individual patients rather than to global models of disease. This trend will also allow for reconciliation with anti-psychiatry as the personalization of medical care will grant more user choice: eliminating the urgency of many of anti-psychiatry’s protests against psychopharmaceuticals. The dissolution of broad diagnostic criteria will render obsolete the criticisms about the insolvency of psychiatry’s diagnostic system.
Cardiovascular disease is an example of a somatic illness that has already gone through this transformation. The term cardiovascular disease only has meaning in a personal context. Cardiologist Charles Sing indicates that cardiovascular disease “develops as a consequence of interactions between the ‘initial’ conditions, coded in the genotype, and exposures to environmental agents indexed by time and space.” The causes of cardiovascular disease include diet, exercise levels, daily stress, lipid profiles, high blood pressure, poor heart function and many others. Nobody suggests that any of those is contributing factors are inherently more important than any others; these factors are prioritized only to the degree in which they are present in any given patient. Also, few people would argue that they are free of cardiovascular disease; it is understood as a dynamic health condition that should be managed throughout life. Similarly, I suspect that post-psychiatry will adopt treatments strategies incorporating psychopharmaceutical correction of irregular brain function combined with cognitive therapy aimed at assisting individuals in normal construction of the ‘architecture of their mind.’

The Anti-psychiatry Movement

The Contemporary Moment: Psychiatry and its Critics II
Anti-psychiatry is a growing movement, which views modern psychiatry’s commitment to the biomedical model as dogmatic and harmful. The movement has attempted to brand psychiatry as pseudoscience for its perceived unwillingness to objectively consider the evidence against the biomedical model of mental illness. Anti-psychiatry has a bedrock of support in disillusioned psychologists, social workers, and psychiatric survivors who view contemporary psychiatry as “mindless and uncaring,” overly reliant on pharmaceuticals, and hostile to psychotherapy. Critics also claim that contemporary psychiatry is beholden to the pharmaceutical industry. They point to the conflicts of interest that are pervasive in the interactions between psychiatrists, scientific journals, and pharmaceutical industry. In addition to concerns about efficacy, the presence of serious side-effects causes detractors to question the safety and innocuousness of psychopharmaceuticals. Tardive dyskinesia and other extra-pyramidal side effects are significant contributors to the mistrust of psychiatry, and particularly psychopharmaceuticals. Further, the anti-psychiatric movement views psychopharmaceuticals as crude mood suppressors; “chemical lobotomies” that can eliminate outward manifestation of positive symptoms, but do little for negative symptoms or internal disturbances. Anti-psychiatry points to psychiatry’s inability to provide genetic or chemical tests for mental illness as an inability to apply its own paradigm to patients; in short, anti-psychiatry perceives contemporary psychiatry as built upon an unproven biological paradigm.
Dr. Thomas Keen describes the conflict between psychiatry and anti-psychiatry as part of the struggle of Moderninst psychiatry in adapting to an increasingly more post-modern world. He suggests that psychiatry is rooted in “the modernist dark ages of professional authority, clincal certainty” and can not survive in a “post-modern society where central, authoritarian discourses are increasingly collapsing und the challenge of pluralism.” His suggestion is that psychiatry must decentralize; it must acknowledge the criticism of anti-psychiatry and actively include patients or ‘end-users’ in the discursive process of framing pschiatric disorders. This transformation is not unique to pyschiatry, but post-modern assaults on the nature of the mind and consciousness are.
Psychiatrists sense that their discipline is becoming increasingly problematic and unwieldy. That less than 500 new residents join the profession annually demonstrates that the medical profession views the field as stagnant. Yet, for the most part psychiatry clings to essentialism and biological reductionism. It is not uncommon for research papers to end with supplications to future research: “It is hoped that [further] study…will provide new insights into the genetic basis of abnormal behaviour.” Psychiatry remains faithful to the promise that genetics will elucidate the basic molecular and genetic mechanisms behind mental illness disease processes and will provide elegant new targets for pharmacological intervention.

Influenced by

• Thomas Keen. “Post-psychiatry: paradigm shift or wishful thinking? A speculative review of future possibles for psychiatry,” Journal of Psychiatric and Mental Health Nursing, 2003: 32.
• Philip Thomas and Patrick Bracken. “Critical psychiatry in Practice,”Advances in PsychiatricTreatment, 2004: 364.