Sunday, March 15, 2015
Neuroscience and Heisenberg Uncertainty
The current sources of data for neuroscience research are naturalistic data (where there is no intervention and the subjects do not know they are being observed), and experimental data (where there is an intervention, and/or the subjects know they are being observed).
Any naturalistic data may suffer from the fact that it was not specifically designed apriori to answer a particular question. Any experimental data may suffer from the Heisenberg uncertainty principle, where the intervention/observer modifies to some extent what is being observed. That holds true from induced pluripotent stem cells to testing of patients in clinical trials.
What is the solution to circumvent these limitations and transform them into strengths? We believe that a convergent combination of naturalistic data with experimental data has the best yield, and should be programmatically pursued at all levels of neuroscience. For example, in developing tools to predict psychiatric disease outcomes such as suicide, a combination of naturalistic medical records and other life records mining with experimental neuropsychological and laboratory tests will yield the best outcome. Similar arguments can be made for drug development, and so on.
Monday, January 13, 2014
Less is more: the secrets of success in human (psychiatric) genetic and biomarker studies
1. Phenotype
- Study these phenes (for example, mood, hallucinations, suicidality ) in high –risk populations ( bipolar schizophrenia), which provide an enriched pool.
- Study these phenes longitudinally, over time. Wireless devices and mobile health applications are crucial.
2. Cohorts
- When enrolling subjects, for reliability of phene measures use an longitudinal within-subject design whenever possible.- Validate phene measures by the convergence of internal feelings and thoughts ( as measured by self-report scales) and of external actions and behaviors ( as measured by external raters).
- Separate cohorts by gender and by ethnicity, as this homogeneity leads to a reduction in noise.
3. Gene expression (biomarker discovery) is much more powerful than genetics (mutations discovery)
- One expressed gene may integrate the effects of up to ~ 103 SNPs, epigenetic changes, as well as the current effects of the environment.
- Focus on discovering first state biomarkers, correlated with phenes measured at the time of biomarker testing, not trait biomarkers, unless you have good longitudinal phene data. State over time is trait.
4. Study design
- A within -subject design is the best, as it factors out genetic variability. You can do aggregates of n of 1 studies. You may need n~101 for gene expression studies, and n~ 104 for family based genetic studies (the closest you can come to “within-subject” in genetics).
- A case-case design is second best, as it factors out some disease related variability. You may need n~102 for gene expression studies, and n~ 105 for genetic studies.
- A case-control design is the least powerful, due to heterogeneity and noise that is not factored out, i.e. many of the differences do not have something to do directly with the phenotype you are studying. You may need n ~103 for gene expression studies, and n~ 106 for genetic studies.
5. Convergent Functional Genomics (CFG) at a gene level
- ~ 102 more reproducibility at a gene level than at a SNP level.- Reproducibility in independent cohorts is more important than strength of signal in the discovery cohort, as that could be a fit-to-cohort effect.
- CFG is like a magnet that finds the biomarker “needle” in the genetic or blood gene expression “haystack”. It uses in a Bayesian way the whole prior body of work in the field to identify, prioritize and give credence to disease-related genes from the long lists of differentially tagged genes in genetic association studies ( GWAS), and from differentially expressed genes in the brain or blood.
-Moreover, the genes and biomarkers prioritized by CFG are fit-to-disease, not fit to cohort. Because of that, they travel well, reproduce and are predictive in independent cohorts, which is the ultimate litmus test for any genetic or biomarker finding.
Monday, August 12, 2013
How to prevent suicide
Suicidal behavior can occur due to a
combination of existential reasons, biological vulnerabilities, and
environmental factors. The existential reasons include lack of satisfaction
with current life (health, finances, social importance), lack of hope for the
future, and not being/feeling needed (especially by progeny and family). The
biological vulnerabilities include mental health issues and addictions,
including a genetic vulnerability to suicide as reflected in a family history of suicides among biological relatives.
The environmental factors include increased stress and pain (physical and
psychological), as well as cues that enable this behavior (previous attempts,
knowing examples of other people who have done it, living in an environment and (sub-) culture
where suicide is an option, seems attractive, and the means are available).
The opposites of each of the above items
are protective. Individuals can have a mixture of risk factors and protective
factors.
A simple checklist of all these factors,
tabulating risk factors and protective factors, along with improved objective biomarkers,
should lead to very high levels of identification of individuals at risk,
combining specificity with sensitivity of detection. This would permit
preemptive intervention- changing and saving lives.
We are working on that.
Friday, January 11, 2013
Trend of the Year 2013:
Genomics out, biochemistry in, for curing diseases?
Genomic variation and complexity are such that the genetic basis of most human diseases is going to require another decade or more to unravel completely, and even then it will be only partially explanatory, due to the profound role of the environment and of developmental history. Even when driver mutations are found and are targeted by a drug, the disease process may not be completely blocked, and alternative biological pathways may be recruited by the disease, as is the case in cancers.
However, diseases have key "vulnerabilities" at a metabolic and biochemical level that can be therapeutically attacked much sooner than that. Such metabolic targets are the result of the combinatoric integration of myriad mutations and environmental effects. For example, in psychiatry, the use of DHA (an omega-3 fatty acid), may correct membrane, signalling and inflammatory abnormalities that are responsible for vulnerability to stress, anxiety, mood and cognitive symptoms.
Genomics will still be important for scientific understanding in the long run, and for risk stratification and diagnostics in the short run.
Alexander B. Niculescu, III, MD, PhD
Genomics out, biochemistry in, for curing diseases?
Genomic variation and complexity are such that the genetic basis of most human diseases is going to require another decade or more to unravel completely, and even then it will be only partially explanatory, due to the profound role of the environment and of developmental history. Even when driver mutations are found and are targeted by a drug, the disease process may not be completely blocked, and alternative biological pathways may be recruited by the disease, as is the case in cancers.
However, diseases have key "vulnerabilities" at a metabolic and biochemical level that can be therapeutically attacked much sooner than that. Such metabolic targets are the result of the combinatoric integration of myriad mutations and environmental effects. For example, in psychiatry, the use of DHA (an omega-3 fatty acid), may correct membrane, signalling and inflammatory abnormalities that are responsible for vulnerability to stress, anxiety, mood and cognitive symptoms.
Genomics will still be important for scientific understanding in the long run, and for risk stratification and diagnostics in the short run.
Alexander B. Niculescu, III, MD, PhD
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
Subscribe to:
Posts (Atom)