Harold Hillman's 'Unanswered Questions in Biology'

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"47 UNANSWERED QUESTIONS IN BIOLOGY. 27 May 1996. June/July 1996

Dr Harold Hillman writes:–
The only real guarantee of the progress of knowledge is for academics to be ready to enter into unlimited dialogue about their research and theories, especially about those which they have published. An academic who is not prepared to discuss or correspond with other interested parties is behaving improperly, and such conduct should not be tolerated by the academic community. Some colleagues seem to think that if they ignore the awkward questions about their disciplines, or are hostile to those who ask them, the contradictions or anomalies in their work will somehow or other resolve themselves, and their research can progress. On the contrary, such an attitude inhibits the examination of the fundamental aspects of their disciplines, and thus delays substantial progress.
    The following questions have never been answered satisfactorily, several of them never at all:"


Question 1: Can one obtain an enriched fraction of a subcellular organelle or cell type?
Question 2: How does one know that the disruptive procedure does not change the biochemistry of the fraction significantly?
Question 3: Why does one assume that homogenisation and centrifugation do not change the entropy, and therefore the free energy and the equilibria of reactions in subcellular particles? Why are not controls always carried out for subcellular fractionation, except for total recoveries relative to the crude homogenates?
Question 4: Why is it believed that each biochemical pathway or cycle has its own structural compartment when prokaryotes can carry out virtually all the same reactions in only one compartment?
Question 5: Does the finding that a chemical substance or activity is located in the same subcellular fraction and a structure identified by electron microscopy mean that the same chemical activity was located in that particular organelle in the living cell of the intact animal or plant.
Question 6: How is intracellular movement possible, and why is the viscosity of cytoplasm so low in the intact cell, if there is a cytoskeleton present?
Question 7: Where do protein synthesis and acid hydrolysis occur in cells in which ribosomes and lysosomes cannot be seen?
Question 8: What is the evidence that the microsomal fraction consists of cell membranes and endoplasmic reticulum?
Question 9: Why is it assumed that homogenisation and centrifugation do not affect the chemistry of receptors, or their affinities for transmitters, hormones, drugs, ligands, toxins?
Question 10: Can a particle and a vacuole both be lysosomes?
Question 11: Can one calibrate substances originating from tissues using pure solutions in simple salines of approximately the same concentrations?
Question 12: How can one study membranes by electron microscopy, when they are believed to contain lipids which the procedure extracts?
Question 13: What is the real evidence that rapid deep freezing for electron microscopy causes less shrinkage and distortion of tissues, cells and organelles, than classical transmission electron microscopy?
Question 14: Why do those who calculate dimensions from electron micrographs not take into account the shrinkage during preparation and examination of their sections, cells and organelles?
Question 15: Do membranes in cells appear to be normal to the plane of section more often than solid geometry would permit?
Question 16: Can one know the thickness in life of any biological membrane?
Question 17: Why should it be necessary to tilt the stage of the electron microscope to see randomly orientated membranes in all orientations, when this is not necessary with the light microscope?
Question 18: How can carriers assist the passage of ions, aminoacids, etc. across membrane, when the combination must be bigger than the substance carried?
Question 19: Why have few or no carriers been isolated?
Question 20: What is transport?
Question 21: Why are receptors and channels, which have been characterised, sequenced and their sizes measured or calculated, not seen on membranes by transmission electron microscopy?
Question 22: Can an electron microscopist looking at a metal deposit on a biological structure derive any information about its chemistry?
Question 23: Why do the lamellae of the myelin sheath appear to be equal distances apart irrespective of the thickness or depth of the longitudinal section cut?
Question 24: Is the repeating distance of the lamellae in the myelin sheath sufficient to regard it as a good model for the cell membrane?
Question 25: Since the myelin sheath is believed to consist of a scroll of membranes, and membranes appear darker by light microscopy than cytoplasm, why does not the myelin sheath appear darker than the axoplasm?
Question 26: Why is it assumed that the receptors for transmitters, hormones, messengers, antibodies, drugs and toxins are on the surface of the cell membrane?
Question 27: How valid is the use of agonists, antagonists and ligands to detect receptors, instead of the transmitters, hormones, antigens, drugs and toxins themselves?
Question 28: Why are the dimensions and numbers of synapses different by light and electron microscopy?
Question 29: Why are there no light micrographs in the literature showing the connection of one cell body by a dendritic pre-synaptic fibre to a synapse on another cell body?
Question 30: Does the chemical theory of synaptic transmission contain unprovable and unproved hypotheses?
Question 31: Why is it assumed that evidence derived from experiments on neuromuscular junctions is relevant to transmission in the central nervous system?
Question 32: If nuclear pores allow RNA to pass through, how do they prevent smaller molecules and ions going through at the same time, and why is there a potential difference across the nuclear membrane?
Question 33: What is the evidence that each cell of a particular plant or animal contains the same quantity of DNA?
Question 34: If the cell membrane is fluid mechanically, how can cells maintain their integrity?
Question 35: In immunocytochemistry, is it assumed that the fixatives, dehydrating reagents, washings, and primary and secondary antibodies, do not change the reaction of the antibody to the antigen believed to be in a particular cell or part of a cell?
Question 36: Is it reasonable to believe that processes or dendrites contain different antigens from the cell bodies from which they arise?
Question 37: Under what conditions can tissue cultures be used in the study of the tissues from which they originated?
Question 38: Is it warrantable to assume that growth of tissues in culture does not change their morphology, biochemistry, or immuno-reactivity?
Question 39: Does not the use of the term neuroglia imply that the authors can not distinguish between astrocytes, oligodendrocytes, and microglia?
Question 40: Why are the individual types of neuroglial cells so rarely seen by light microscopy of healthy central nervous systems?
Question 41: Since the latter three alleged cell types were described by classical histological techniques during the first half of the twentieth century, does this not imply that anyone using antibodies to mark them specifically must first identify them by these criteria?
Question 42: Why is there no common agreement about the staining procedures, which are supposed to identify astrocytes, oligodendrocytes and microglia histologically?
Question 43: Why is it necessary to use tissue cultures of the alleged cell types to identify them and their markers?
Question 44: If each cell in an organism contains the same DNA, but some produce different proteins, is the existence of suppressor genes the only possible explanation for the difference of the proteins?
Question 45: In diseases believed to be auto-immune, either organ-specific or tissue-specific, why does the body not reject the specific organ or tissue, as it rejects incompatible transplanted hearts, or blood of the wrong group, often making the patients ill, or even killing them?
Question 46: Why are pure proteins used for calibration, when different tissues contain different mixtures of proteins, which have different calibration curves?
Question 47: Why do synapses seen by electron microscopy appear so much smaller than those seen by light microscopy?


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