Wednesday, October 24, 2012
Science(-fiction) musings on how to achieve longevity and immortality
Prevention:
1. Store regenerative material at a younger age (umbilical cord, sperm/oocytes, iPS).
2. Live a healthy lifestyle to minimize damage. Avoid toxins, build resilience.
Treatment:
1. Treat early on and aggressively any abnormality.
2. Replace body-parts as need be with (self-) regenerative medicine or bionic prostheses.
Transcendence:
3. Create a legacy through your progeny, your life’s work, and through educating/influencing others.
4. “Download” your mind to a cloud computer website/app when your body eventually fails beyond repair, like a car with too many miles. Put all your legacy of knowledge and wisdom online. Your mind computer app will continue to interact with and advise your progeny, kin, and the world at large.
Saturday, March 31, 2012
Reasons for the increased incidence of autism (and other brain disorders)
The reasons for the increased incidence of autism and other disorders are two-fold: on the one hand we have increased awareness and diagnosis, on the other hand we have a genuine increase in the incidence of disease.
The genuine increased incidence of disease is due to three factors: age, quantity and fit. Age refers to older parents, in which there is increased incidence of DNA mutations in spermatocytes and oocytes. Over 80% of the genes in the genome are involved in brain function, providing plenty of targets in which random mutations can occur that may affect brain function. Quantity refers to increased environmental exposure to factors that affect brain development and growth, including for autism possible chemicals in the environment and nutritional factors that promote a diabetes-like state in mother and fetus. Fit refers to the fact that there is an increased preservation and selection in the population of gene variants involved in mental functions, which are the same gene variants that, if you have too many of them, in the wrong combination and in the wrong environment, can lead to psychiatric disorders such as autism, schizophrenia or bipolar disorder (what we call in our group the 4C x E model of disease- contextual cumulative combinatorics of common gene variants and environment).
Our best estimate so far, is that autism is a disease of connectivity, based on the body of evidence in the field, and comparative genomics of schizophrenia and autism (see for example Ayalew, Le-Niculescu et al. Molecular Psychiatry 2012 In Press). We think that autism is a disease of localized increased connectivity in the brain (abnormal or supra-normal), and overall decreased connectivity to the environment, hence the occasional very high levels of performance on specific tasks but overall social problems. Schizophrenia may have localized abnormal increased connectivity in certain brain circuits (leading to hallucinations, delusions and paranoia), but overall is characterized by much more decreased connectivity in the brain and with the environment, hence the occasional increased creativity but overall poor social functioning if left untreated.
The solution for both disorders is to modulate the age, quantity and fit factors. Parents should conceive at an earlier age or at least store their germinal cells in youth for later conception. Environmental factors that affect brain development and growth should be identified ( stress, inflammation, infections, head trauma, drugs, nutritional factors, chemical pollution), avoided and mitigated against with early preventative treatments. The continued increased selection and enrichment of genes involved in increased mental performance is unavoidable in our current information-driven era (where the brain is our main tool and reason for professional success), but genetic testing for possible early intervention, coupled with brain exercises and better treatments to minimize the deficits, and a greater appreciation and tolerance for diversity and specific skill sets, should make most individuals into content and productive members of society!
Alexander B. Niculescu, MD, PhD
The genuine increased incidence of disease is due to three factors: age, quantity and fit. Age refers to older parents, in which there is increased incidence of DNA mutations in spermatocytes and oocytes. Over 80% of the genes in the genome are involved in brain function, providing plenty of targets in which random mutations can occur that may affect brain function. Quantity refers to increased environmental exposure to factors that affect brain development and growth, including for autism possible chemicals in the environment and nutritional factors that promote a diabetes-like state in mother and fetus. Fit refers to the fact that there is an increased preservation and selection in the population of gene variants involved in mental functions, which are the same gene variants that, if you have too many of them, in the wrong combination and in the wrong environment, can lead to psychiatric disorders such as autism, schizophrenia or bipolar disorder (what we call in our group the 4C x E model of disease- contextual cumulative combinatorics of common gene variants and environment).
Our best estimate so far, is that autism is a disease of connectivity, based on the body of evidence in the field, and comparative genomics of schizophrenia and autism (see for example Ayalew, Le-Niculescu et al. Molecular Psychiatry 2012 In Press). We think that autism is a disease of localized increased connectivity in the brain (abnormal or supra-normal), and overall decreased connectivity to the environment, hence the occasional very high levels of performance on specific tasks but overall social problems. Schizophrenia may have localized abnormal increased connectivity in certain brain circuits (leading to hallucinations, delusions and paranoia), but overall is characterized by much more decreased connectivity in the brain and with the environment, hence the occasional increased creativity but overall poor social functioning if left untreated.
The solution for both disorders is to modulate the age, quantity and fit factors. Parents should conceive at an earlier age or at least store their germinal cells in youth for later conception. Environmental factors that affect brain development and growth should be identified ( stress, inflammation, infections, head trauma, drugs, nutritional factors, chemical pollution), avoided and mitigated against with early preventative treatments. The continued increased selection and enrichment of genes involved in increased mental performance is unavoidable in our current information-driven era (where the brain is our main tool and reason for professional success), but genetic testing for possible early intervention, coupled with brain exercises and better treatments to minimize the deficits, and a greater appreciation and tolerance for diversity and specific skill sets, should make most individuals into content and productive members of society!
Alexander B. Niculescu, MD, PhD
Monday, January 2, 2012
Trend of the Year 2012: Living in truth- from science to society
2012 will be the year when some of the previous visionary advances become reality through better execution, and others are revealed to be empty hope and fall by the wayside. The contextual cumulative combinatorics and integration of existing methodologies and knowledge from disparate domains will lead to major advances in scientific understanding, diagnostics, and pharmaceutical drug development. The work necessary for such advances will be precise and tedious, but the results will be spectacular.
Discovery-based non-hypothesis driven science carried out in well established laboratories, primarily in developed countries, will lead to real advances, as opposed to the mass of more hypothesis-driven science (and clinical trials) of dubious reproducibility carried out by career-driven less established researchers, primarily in ( and from) developing nations. The issue of ethics and not cutting corners will become as prominent in biomedical sciences and pharma industry as it has been in the last few years in business and finance.
All in all, a solid year ahead.
Alexander B. Niculescu, MD, PhD
Discovery-based non-hypothesis driven science carried out in well established laboratories, primarily in developed countries, will lead to real advances, as opposed to the mass of more hypothesis-driven science (and clinical trials) of dubious reproducibility carried out by career-driven less established researchers, primarily in ( and from) developing nations. The issue of ethics and not cutting corners will become as prominent in biomedical sciences and pharma industry as it has been in the last few years in business and finance.
All in all, a solid year ahead.
Alexander B. Niculescu, MD, PhD
Wednesday, November 2, 2011
The color blue for promoting mental health initiatives
The breast cancer community has done a terrific job of decreasing stigma, raising funds for research and treatment, and increasing awareness using the color pink in marketing and promotional campaigns. We should learn from them.
Mental health is as important an issue for women -and men, but less well publicized. I would propose we use blue as a color for mental health in marketing and promotional campaigns, for exactly the same reasons as in breast cancer- to decrease stigma, raise funds and increase awareness.
In popular culture, blue has already been associated with depression (“having the blues”), or it’s opposite (“blue sky thinking”). It is a soothing color that may decrease anxiety and increase cognition. So the full triad of major mental health domains (anxiety, mood and cognition) can be linked to blue and be well represented by it. There is some research supporting its use as well: http://www.guardian.co.uk/education/2008/jun/24/highereducation.improbableresearch
Who wants to help promote this? Email us and spread the word.
Alexander B. Niculescu, MD, PhD
Mental health is as important an issue for women -and men, but less well publicized. I would propose we use blue as a color for mental health in marketing and promotional campaigns, for exactly the same reasons as in breast cancer- to decrease stigma, raise funds and increase awareness.
In popular culture, blue has already been associated with depression (“having the blues”), or it’s opposite (“blue sky thinking”). It is a soothing color that may decrease anxiety and increase cognition. So the full triad of major mental health domains (anxiety, mood and cognition) can be linked to blue and be well represented by it. There is some research supporting its use as well: http://www.guardian.co.uk/education/2008/jun/24/highereducation.improbableresearch
Who wants to help promote this? Email us and spread the word.
Alexander B. Niculescu, MD, PhD
Monday, July 25, 2011
Psychiatric genetics: contextual cumulative combinatorics of gene variants and environment
Classic genetics research in psychiatric disorders has provided an abundance of data but a paucity of insight. Things will only get worse in terms of this ratio, as massive sequencing of genomes becomes routine.
The reasons are four-fold. First, psychiatric disorders are genetically complex, with many (hundreds, if not thousands) genes involved. We first proposed that over a decade ago, based on our pioneering gene expression work cross-matched with human genetic data (Convergent Functional Genomics). Second, psychiatric disorders are genetically heterogeneous, with different mutations in the same gene present in different individuals. Many of these mutations are in fact common variants present in non-psychiatrically ill individuals as well. Third, psychiatric disorders as currently defined by DSM are overlapping and interdependent, with genes and biological pathways shared among disorders. Fourth, the environment plays a major role in modulating gene expression and the development or not of illness.
The key to progress is to acknowledge reality in the four areas mentioned above. Illness or lack of illness are the result of cumulative combinatorics of common gene variants and environmental stressors (or favorable factors). Genetic context and environmental context are important to whether a mutation contributes or not to the illness. Gene expression studies are more informative than classic genetics, as they reflect the actual results of the interaction between genes and environment, and underlie the subsequent patho-physiological outcomes. Biological pathways and mechanistic-level analyses will show more commonality and reproducibility across individuals, and from study to study. A dimensional approach to psychiatric profiling of individuals will eliminate the confusion and overlap of DSM, as well as permit a better mapping and tracking of biological reality. Our group has provided comprehensive proof and solutions over the years in all these areas, and we will continue to do our bit.
Alexander B. Niculescu, III, MD, PhD
The reasons are four-fold. First, psychiatric disorders are genetically complex, with many (hundreds, if not thousands) genes involved. We first proposed that over a decade ago, based on our pioneering gene expression work cross-matched with human genetic data (Convergent Functional Genomics). Second, psychiatric disorders are genetically heterogeneous, with different mutations in the same gene present in different individuals. Many of these mutations are in fact common variants present in non-psychiatrically ill individuals as well. Third, psychiatric disorders as currently defined by DSM are overlapping and interdependent, with genes and biological pathways shared among disorders. Fourth, the environment plays a major role in modulating gene expression and the development or not of illness.
The key to progress is to acknowledge reality in the four areas mentioned above. Illness or lack of illness are the result of cumulative combinatorics of common gene variants and environmental stressors (or favorable factors). Genetic context and environmental context are important to whether a mutation contributes or not to the illness. Gene expression studies are more informative than classic genetics, as they reflect the actual results of the interaction between genes and environment, and underlie the subsequent patho-physiological outcomes. Biological pathways and mechanistic-level analyses will show more commonality and reproducibility across individuals, and from study to study. A dimensional approach to psychiatric profiling of individuals will eliminate the confusion and overlap of DSM, as well as permit a better mapping and tracking of biological reality. Our group has provided comprehensive proof and solutions over the years in all these areas, and we will continue to do our bit.
Alexander B. Niculescu, III, MD, PhD
Saturday, July 2, 2011
Clock Genes and Mood
"There can be no transforming of darkness into light and of apathy into movement without emotion"
- Carl Jung
After more than a decade of work on understanding mood, using the magnifying glass of severe mood dysregulation disorders such as bipolar disorder, our group has proposed and provided evidence for mood being related to levels of activity, energy and growth, in response to internal and external environment cues. When the environment is favorable, levels of activity and growth are (or should be) high. When the environment is unfavorable, levels of activity are (or should be) low. When there is a discongruence between levels of activity of the organism and the environment, we are dealing with a mood disorder, manifested as depression or (hypo)mania.
Following early hypotheses from W. Bunney and R. Lennox, our group has provided over the last decade cumulative empirical evidence that supports a model where circadian clock genes are the core mechanism of mood regulation and dysregulation. They serve as a thermostat, increasing or decreasing the level of activity of cells, brain and of the whole organism. Some key circadian clock genes we have identified and provided evidence for involvement in mood are ARNTL, RORB, and DBP. DBP, first identified by us as a candidate gene for bipolar disorder over a decade ago, has provided a basis for us developing the first broad-spectrum genetic mouse model of bipolar disorder, which mimics both phases of the illness, depression and mania, as well as mimics the sensitivity to stress and the propensity to substance abuse.
Due to the genetic overlap and biological interdependence between mood, anxiety and cognition, circadian clock genes have also appeared in screens conducted by us and others for genes involved in other disorders, such as anxiety disorders and schizophrenia. It is understandable how levels of energy (mood) can influence signal transduction reactivity (anxiety) or brain connectivity (cognition).
Clock genes are present in every cell in the body, regulating the expression of thousands of other genes. They are likely going to become key targets for therapeutic intervention and new drug development, and provide a biological rationale for circadian medicine, circadian psychiatry, and other subspecialties of the future.
Clock genes are present in every cell in the body, regulating the expression of thousands of other genes. They are likely going to become key targets for therapeutic intervention and new drug development, and provide a biological rationale for circadian medicine, circadian psychiatry, and other subspecialties of the future.
Alexander B. Niculescu, III, MD, PhD
Saturday, March 5, 2011
The Biomarkers Solution: How to Improve Pharma Drug Discovery
The drug discovery process is currently flawed at both pre-clinical and clinical levels. Biomarkers are an emerging “bridge over troubled waters” between these two areas, and a solution for their respective ills.
Preclinically, gene expression networks, not single gene products, need to be targeted for comprehensive and successful treatment of diseases. Combinations of drugs need to be developed and used from the beginning for broad impact. Profiling baseline gene expression and response to drugs in animal models using biomarkers can ensure the right combinations of drugs are selected and advanced towards clinical testing.
Clinically, one size does not fit all. The blockbusters of the future will not be blockbusters in terms of patient population sizes treated, but rather due to precision and efficacy, commanding a deserved premium price that way. Some of the same biomarkers derived from discovery work and pre-clinical studies can be used in clinical studies, providing solutions for their current limitations: better diagnosis and patient stratification, objective monitoring of response to treatment, and a handle on the placebo effect. Early biomarker information from clinical trials will provide in an iterative fashion intelligence for improved selection criteria and outcomes in later clinical trials, leading to an enhanced rate of successfully approved medications, albeit for more narrow indications.
Alexander B. Niculescu, III, MD, PhD
Preclinically, gene expression networks, not single gene products, need to be targeted for comprehensive and successful treatment of diseases. Combinations of drugs need to be developed and used from the beginning for broad impact. Profiling baseline gene expression and response to drugs in animal models using biomarkers can ensure the right combinations of drugs are selected and advanced towards clinical testing.
Clinically, one size does not fit all. The blockbusters of the future will not be blockbusters in terms of patient population sizes treated, but rather due to precision and efficacy, commanding a deserved premium price that way. Some of the same biomarkers derived from discovery work and pre-clinical studies can be used in clinical studies, providing solutions for their current limitations: better diagnosis and patient stratification, objective monitoring of response to treatment, and a handle on the placebo effect. Early biomarker information from clinical trials will provide in an iterative fashion intelligence for improved selection criteria and outcomes in later clinical trials, leading to an enhanced rate of successfully approved medications, albeit for more narrow indications.
Alexander B. Niculescu, III, MD, PhD
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