Nobel Prize, anyone?/ The cell-centric perspective.
Revised 2015, May 24
The tabula rasa doctrine
The tabula rasa assumption is the central issue in epistemology:
* It underlies present-day knowledge
* It has proved to be empirically false
* The philosophic community is not yet ready to respond to the crisis
Application of the tabula rasa doctrine to the cell. The term tabula rasa is normally applied to the mind and brain. It applies to the cell as well, and in particular to the neuron:
* The emphasis on memory, learning, networks, neurotransmitters and synapses implies the assumption that cells, prior to input, are blank slates.
* The genome, epigenome and the transcriptional mechanisms are intracellular, and so is the causal locus
* Whatever is true of all cells in an organism is true of brain cells.
Conclusion. the next major stage in biology and neuroscience is the recognition of the cell-type intrinsic function
Genetics, neuroscience and medicine are conceptually outdated. In the ten years between 2002 and 2012 some 230 Alzheimer’s diisease drugs failed. The techniques applied to the development of those drugs have been excellent. The failure has been conceptual. We address here the conceptual issue.
Life. Erwin Schrödinger (1944), using top-down reasoning, reached the conclusion that life requires, and therefore must have, chemically stable, information-rich molecules. These turned out to be DNA (1953). However, it is the cell that is the smallest unit of life: cells are made of lifeless molecules. The discovery of the structure of DNA neither answered nor addressed the question what cell-specific properties constitute life. Listed below are some fundamental concepts that ought to be incorporated in the characterization of what is life.
Homeostasis. Biology is not exempt from physics. Physical systems move from less probable to more probable distribution. Therefore, fluctuations in the external environment are expected to affect the internal environment of living systems. But they do not. Claude Bernard (1878/1974) noted and called attention to this remarkable fact, concluding that life must involve mechanisms that detect and correct departure from stasis. Walter B. Cannon (1923) named that mechanism homeostasis.
Homeostasis as negative feedback mechanism. In “Behavior, Purpose and Teleology” (1943), Rosenblueth, Wiener, and Bigelow showed that 1) the notion of negative feedback, being mathematically precise, is conceptually the right tool to account for homeostasis, and 2) that negative feedback systems are, in fact, goal-oriented systems.
Applying entropy and homeostasis to information.Claude Shannon’s Mathematical theory of communication (1948) made possible the extension of the notion of entropy from physical systems to information. Consider DNA replication: identical strands would constitute stasis while non-identical strands would constitute disruption. Life would not have been possible if not for the error-detection and correction mechanisms that are involved in DNA replication (and elsewhere). This example illustrates the validity and value of extending concept homeostasis to biological information.
Application of the above notions to life and evolution.
The cell. The cell, while alive, contains homeostatic mechanisms that detect and, within limits, correct departures from set points for multiplicity of variables (e.g. glucose homeostasis). Each such set point is characteristically far from thermodynamic equilibrium (e.g. cell’s “resting” potential)
Information stasis. The homeostatic error-detection and correction mechanisms of the cell extend to information molecules (e.g. DNA replication).
Negative feedback. Operation of negative feedback mechanisms to restore departure from set points is goal-oriented. Explanations in biology and psychology are, ultimately, goal-oriented.
Toward an improved concept of life. The new definition of what is life would be a concept more general and more precise than any of the mechanisms listed above. That new definition of life would complement and counteract the diversity of ways that entropy increase can affect organisms (e.g. the immune system).
Toward an improved notion of evolutionary success. The main thrust of evolution is periodic improvement in the entropy-fighting mechanism of species so that they can survive in greater diversity of environments: evolution, apart from niche adaptations, has a direction. Consider temperature homeostasis in mammals. It requires a huge (nearly tenfold) increase in energy consumption and expenditure. Chemical processes are temperature-dependent. Temperature homeostasis makes possible brain function in temperature range outside what is available to non-mammalian organisms. Temperature homeostasis extended the range of environments in which mammals can survive. This evolutionary direction is unrelated to the notion that evolutionary success is in out-procreating other species.
Cell-types of multicellular organisms
The cell-types of the body. The cell is the basic unit of life. Its genome encodes the proteins that can be expressed in a given organism. In multicellular organisms the cell-type is the basic unit of intrinsic function. The cellular epigenome is the subset of proteins encoded by the genome that can be expressed in a given cell-type. The cellular proteome is the subset of the epigenome proteins that are actually expressed in that cell-type. Proteins common to all cell-types, the so-called ‘housekeeping proteins,’ often vary in a cell-type-specific manner. For example, visual motion-direction cortical columns in visual area V5/MT can be identified by their higher mitochondria count than surrounding cells. The molecular constitution of a cell-type is a determinant of its phenotype and its intrinsic function.
Phenotype and molecular constitution of cell-types. By phenotype, the human body contains some 220 different cell-types. Each phenotypic cell typically represents numerous subtypes by molecular constitution. For example, in humans, the phenotypic olfactory receptor cell represents some 350 subtypes. Each subtype contains the Olfactory Marker Protein as well as a protein that is subtype-specific.
Misdirection of neuroscience, genetics and medicine
The legacy of J. B. Watson, K. S. Lashley, and D. O. Hebb
John B. Watson (1913). Watson proposed that behavior is to be explainedwithout reference to the brain.
Karl S. Lashley (1929). Lashley reached the mistaken notions that cell locus and cell type are not causally significant factors in accounting for brain function.
Donald O. Hebb (1949). Hebb accepted Lashley’s mistaken findings. He therefore concluded that if the cells do not determine function then it must by cell assemblies (i.e. interconnections and interactions).
Epistemological legacy. Present-day neuroscience, genetics and medicine are still prisoners of that epistemological legacy.
The casual locus of function is intracellular
The distinction between proximal and non-proximal causes. A cause and effect relation may be viewed as a spatiotemporal sequence beginning with a distal event and culminating with a proximal causal link, which triggers the effect. In such causal chains, the proximal cause link is sufficient to trigger the effect. Any such proximal causal link may be brought about by any number of non-proximal causal links. In this sense, the non-proximal causal chain is contingent, not necessary. The spatial non-proximal causal chain may be thus detached, and replaced by a local proximal cause. To that extent the environment is a detachable non-proximal cause.
Modulation of gene expression. Modulation of gene expression is central mechanism in the regulation of cellular function. The genome, epigenome, transcriptional mechanism, and the spliceosome are intracellular, and in eukaryotic cells they are also intranuclear. When the cell regulates its internal environment, then both the environment and the causal locus of regulation are intracellular.
Cell-type protein-specificity determines phenotype. The 'protein-specificity’ and ‘proteome’ of a cell-type are used here interchangeably. Cell-type protein-specificity is the primary determinant of the cell’s phenotype and intrinsic function. Change in cell-type protein-specificity is a downstream consequence of the cell’s modulation of gene expression. The initial response of cells to stimuli takes a fraction of a second while gene expression takes minutes. For this reason, it is the protein-specificity rather than the epigenome that determines initial intrinsic response (e.g. a sensation in response to external stimulus).
Protein function and laws of nature. The laws of nature that determine the function of proteins are not encoded in genes. Proteins fold faster than can be computed by the most powerful computers. This fact suggests that we know some but not all of the laws that are involved.
Mapping protein specificity of cell types of the body is job 1
Mapping the cell-type protein specificity of the body would make it possible to determine:
* the number of cell-types in a tissue, organ, or the body
* the difference of cell-types relative to a common denominator
* the phenotype as a manifestation of the cellular proteome
* cell-type-specific intrinsic function
Doing so would transform biology from the current, pre-theoretic state to a theoretic discipline. That, in turn, would mark the dawn of a new day in neuroscience and medicine.
Intrinsic function of neurons. The production of circadian rhythmoutput by hypothalamic cells is their intrinsic function: these cells can produce that rhythm also in vitro. Hence, computational models that are based on the assumption that the output of cells is computable from their inputs alone are false. What is now needed is to demonstrate that intrinsic function is a basic cell-type attribute, rather than an exception. One way to do this is by demonstrating a one-to-one correspondence between the protein-specificity and the intrinsic function of cell-subtypes.
A proposal. Apparently, the best way to establish a one-to-0ne correspondence between the protein-specificity and intrinsic function of cell-subtypes is to first identity the protein-specificity of the 3,500 inner hair cells (IHCs) in each ear. These hair cells are the transducers that convert air vibrations to neural impulses. Doing so will be the very first time that a one-to-one correspondence is demonstrated between intrinsic function and its protein-specificity of cells.
Why inner hair cells? The auditory sensation of pitch has some unique attributes:
* The range of auditory pitch sensations represents a one-dimensional array.
* Air vibration varies gradually; pitch sensations are discrete.
* Musical notes are recognizable as the same over ten doublings of air vibration frequency (octaves).
Like strings in a musical instrument, the relative height of any IHC correlates with its characteristic frequency where the higher frequencies are represented by shorter hair cells. If IHCs can be made to demonstrate their characteristic frequency in vitro, it would prove that the characteristic frequency of any IHC is its intrinsic function. Such a demonstration, taken together with the three attributes of auditory pitch listed above, would make IHCs the best choice for mapping one-to-one correlation between protein-specificity and intrinsic function of cells.
The ten octave-specific frequencies of the semitone A. An octave is a doubling of a given frequency. Thus, the 20Hz – 20kHz range involves ten doublings (i.e. octaves) from the lowest to the highest audible frequency (at 40-decibel loudness). The conventional musical scale divides an octave into twelve semitones. These twelve semitones recur at every octave. Consider the semitone A. In the lowest frequency octave it is 27.5Hz. Listed below are the ten octave-specific frequencies of the ten A semitones:
A necessary step toward identifying the neural correlates of consciousness (NCC). The recursion in subjective states shown above reflects a correlated recursion of protein-specificity. In conjunction with the one-dimensionality of vibration frequencies and the step-like transition from one pitch to the next, this recursion makes hearing the optimal sensory modality for identifying the physical determinants of subjective states, commonly called NCC. However, such a project cannot be successfully undertaken unless first the intrinsic function of cell-types is recognized.
Some epistemological consequences
The recognition of cell-type-specific intrinsic function would have epistemological consequences and change research priorities:
Cell-type databases. The protein specificity of cell types of the brain and body would be mapped and be made available on publicly accessible databases.
NCC. The non-exclusion of intrinsic function would make possible, for the first time to establish a one-to-one correlation between cellular cluster and behavioral or an elementary mental state.
The computer model of the brain. Recognition of the structure function relation of cell-type molecules should bring to an end the mistaken notion that an algorithm can realize a mental state.
New York University
An Open Letter To The President
Honorable President Barack Obama
The White House
1600 Pennsylvania Avenue NW
Washington, DC 20500
Dear Mr. President:
I have been troubled by the continued failure of medicine to effectively address chronic diseases, and with the resulting crushing economic burden. I graduated this year from New York University with a B.S. in Neural Science and a concentration in Molecular and Cellular Biology.
The enclosed outline of my proposal indicates how chronic diseases that are currently deemed incurable may be prevented. Economically, the proposal makes possible health-care savings of about one trillion dollars per year at the current level of expenditure. I am taking a year off from school and laying out my proposal in greater detail. I intend to send you a preliminary version of my proposal by the end of February 2012.
I believe that the enclosed proposal can make a difference. I hope that it will receive due consideration.
November 29, 2011
Natasha Kharas * New York University * email@example.com * (917)688-9914
How Disease Prevention Can Save $1 Trillion Per Year
The steady and rapid growth of health-care cost as a percentage of GDP has become a crushing burden on the economy. The present focus on improved diagnosis and treatment cannot solve this economic problem. Incurable genetic, epigenetic and life-style diseases can be prevented. I propose that the transition be made from treatment to prevention. I believe that on inspection, the proposed transition to disease prevention would prove to be the only economically sustainable way to address public health.
Genetic and Epigenetic Tests
I propose that a nationwide standard genetic test be introduced in 2014. This test should then be extended periodically. Initially, the test may include the 2% of the genome that codes for proteins. It should be then extended, first to include the whole genome, and then also to include heritable epigenetic factors. Such tests paired with counseling would provide prospective parents with the information and choice pre-conception about children that could have life-threatening diseases.
Saving: Instituting these tests would prevent the expression of the diseases, eliminating treatment costs of children for the diseases included in the tests. It would reduce indirect productivity losses of those that take care of affected children.
Electronic Medical Records (EMRs)
The EMR is mandated to be in use by 2014. I propose that the results of the genetic/epigenetic tests be made a part of the EMR. The specifications for the EMR ought to be modified accordingly. The Social Security card should contain a semiconductor memory chip. Such a memory chip has the memory capacity to contain an essential minimum of the EMR data including encrypted genetic/epigenetic data in machine-readable form.
Saving: Currently data re-entry accounts for most of $1 billion a day spent on health care information processing. This need of repeatedly re-entering data would be eliminated once a Social Security card with a memory chip is introduced, resulting in saving half of this cost factor.
Inducing Healthier Lifestyles
Incentive-related guidelines should be issued to induce lifestyle changes including a healthy diet and an active lifestyle. Healthy lifestyle information ought to be part of curricula at all education levels. Exercise regimen and healthier food should be encouraged in workplaces.
Saving: Instituting these changes would reduce obesity-related diseases such as diabetes and cardiac diseases. It would also reduce diseases linked to alcohol, nicotine and drug abuse. Lastly, it would reduce direct productivity losses, as less of the working population would fall ill.
1. Testing prospective parents would allow elimination of treatment costs of avoided diseases.
2. Introducing the new Social Security card would save half of the information processing cost.
3. Inducing a healthier lifestyle would further reduce cost of disease treatment.
4. Genetic testing and lifestyle changes combined would reduce direct and indirect productivity losses, which are greater than the health care treatment costs in most cases.
At the current level of health care expenditure, the implementation of the proposal would save an estimated $1 trillion per year.
Natasha Kharas * New York University * firstname.lastname@example.org * (917)688-9914
The crisis in present-day medicine. At present, cancer is incurable once it has spread in the body. Similarly, Alzheimer’s disease, diabetes, and rheumatism, as well as many other neurodegenerative diseases, are not curable. In many cases, medicine offers treatment to alleviate symptoms and at times delay the end of life. The economic cost of lifelong symptom-alleviating treatment is enormous. The introduction of electronic medical records, the reduction of health insurance costs, and the improvement in life styles all have merit; however, if any of these are successfully applied, it would not be sufficient to prevent bankruptcy of the economy. At present, Medicare funds are projected to run out by 2017.
The main necessary step. The crucial step is to re-direct medical research from alleviating symptoms and toward prevention and cure. There is no other way. It is crucial to note that molecular biology has made available for some years now the scientific knowledge for such transformation of medicine.
Forcing change. Inertia is a guiding force in institutional life. Two forces can bring about necessary change: a crisis or top-down executive authority. It is universally agreed that the health crisis is grave. What is now needed is the exercise of presidential authority. The National Institute Health of must be directed and authorized to implement the new medical research policy as a matter of urgent national interest.
Cell types of the human body. The cell is the basic unit of function and dysfunction. By phenotype, there are about 220 cell types in the human body. Molecular biology of the cell provides the concepts and methods to identify these cells in terms of their molecular constitution. This has not been done yet. This remarkable fact reflects the different focus of present-day medical research.5.
The transition from pre-theoretic to scientific phase of a discipline. Atomic theory has made it possible to identify differences between chemical elements by reference to a common denominator – the number of protons in their nuclei and number of electrons in their outer shell. In the pre-theoretic stage, chemicals were described simply by their differences. At present, cell types are characterized by differences. In this sense, present-day medicine is still in a pre-theoretic phase.
Molecular biology of the cell and transformation of medicine. Molecular biology of the cell is the basic science of life. DNA is the common denominator relative to which species, haplotypes, and individuals can be identified. The continuously, or constitutively, expressed protein identifies cell type and its developmental stage. The departure of a cell type from its characteristic protein specificity is the simplest and most general characterization of dysfunction. The identification of the protein specificity of mature, non-dysfunctional cell types of the human body would transform medicine from pre-theoretic to scientific stage.
The necessary first step. The identification of the protein specificity of mature, non-dysfunctional cell types of the human body would make possible, for the first time, the systematic development of diagnostics, cures, or prevention of those diseases which at present can neither be diagnosed nor cured.