This document proposes a new unified theory of disease based on the Jones-Ray effect, which describes how certain salts affect the surface tension of water. It suggests that the Jones-Ray effect influences interfacial tensions in the body, which are important for processes like cell engulfment and signaling. Electron micrographs show how cholesterol sulfate can stabilize red blood cell membranes by reducing water stress at interfaces. The theory posits that membrane-bound water exhibits quantum properties and waves that resonate between exclusion zones and cell membranes. Maintaining optimal interfacial tensions may be clinically significant for conditions like membrane stability and neuroreceptor function.

1. Towards a New Unified Theory of
Disease – The Clinical Significance
of the Jones-Ray Effect

2. Robert M. Davidson1 and Stephanie Seneff 2
1Internal
Medicine Group Practice, PhyNet, Inc.
Longview, TX 75605, USA; E-Mail:
patrons99@yahoo.com
2Computer Science and Artificial Intelligence
Laboratory, MIT, 32 Vassar Street, Cambridge, MA
01890, USA; E-Mail:
seneff@csail.mit.edu
2

3. Outline
• Zeta Potential
• The Riddick Effect
• The Jones-Ray Effect
• The Hofmeister Effect
• Coherence Domains
• Interfacial Tension and Engulfment
• Free Energy of Engulfment
• Interfacial Water Stress (IWS)
• Wave Phenomena, Energy and Water Stressors
• Quantum-coherent Bio-interfacial Waves
• Electron Micrographs Illustrating Phenomena
• Clinically Important Observations
• Summary and Take-away Message
3

4. Zeta Potential, defined
“the electrical potential drop from the particle
surface across the bound fluid, to the interface
where the liquid begins to flow under the
shear stress.”
“the ‘zeta potential’ is the potential at the
surface boundary between the stationary fluid
and the liquid that is moving with the
particle.”
- Tigrek and Barnes (2010)
4

5. The Riddick Effect
Zeta potential data for various electrolytes in an anionic colloidal suspension of 100
ppm Minusil . Data were originally published per Thomas M. Riddick (1968) and is
reproduced with permission of Zeta-Meter, Inc. 5

6. The Jones-
Ray Effect
The points are the original data from 1937 by Jones and Ray [154]. The change in the
surface tension of all 13 Jones-Ray salts were fitted to a simple model by Petersen and
Saykally (2005). Reproduced here with permission from Journal of the American Chemical
Society. 6

7. Fluctuations and the Hofmeister Effect:
A Brief History
• Hofmeister (1888) ordered anions according to their ability to precipitate
globular proteins from water.
• Setschenow (1889) established an empirical law linking the solubility of a
protein with cosolute (salt) concentration .
• Heydweiller (1910) discovered that salt dissolved in water increased the surface
tension of the solution-air interface .
• Langmuir (1917) was the first to attempt a theoretical explanation of the
physical mechanism behind the increase in surface tension produced by
electrolytes.
• Der et al. (2007, 2008), instead of focusing on air-water surface tension, used
protein-water interfacial tension as a general description of the free energy
changes associated with salt-induced changes of protein solubility and
conformation . 7

8. The Fluctuation-Dissipation Theorem
• First proven by Callen and Welton in 1951.
- Describes how dissipative forces and fluctuating
random forces are connected.
• Fluctuations in protein conformation are linked to
interfacial tension and protein structural stability.
• Many proteins oscillate between “open” and “closed”
conformations
- Implies water-exposed surface area changes.
• A general relationship exists between salt concentration
and protein-water interfacial tension.
- Plays a key role in protein structure and dynamics.
- Unfolded protein response is a common stressor
leading to cellular apoptosis.
8

9. QED Coherence in Matter
Giuliano Preparata’s (1942-2000) QED Coherence in Matter [1995]
provides the basis for understanding the Stable, Non-Equilibrium
System we call Life
9

10. Embryological Envelopment is Biophysically-driven
DAH – Steinberg’s Differential Adhesion Hypothesis
DITH – Brodland’s Differential Interfacial Tension Hypothesis
R. A. Foty, C. M. Pfleger, G. Forgacs, and
M. S. Steinberg. Surface tensions of
embryonic tissues predict their mutual
envelopment behavior.
Development, 122(5):1611–20, 1996. 0950-
1991
Schoetz, E., Dynamics and Mechanics of
Zebrafish Embryonic Tissues. Der Fakultat
fur Physik der Technischen Universitat
Dresden, 2007.
Brodland, G. W., The Differential Interfacial
Tension Hypothesis (DITH): a comprehensive
theory for the self-rearrangement of embryonic
cells and tissues. Journal of biomechanical
engineering 2002, 124 (2), 188-97.
10

11. Moore, P. L.; Bank, H. L.; Brissie, N. T.;
Spicer, S. S., Phagocytosis of bacteria by
polymorphonuclear leukocytes. A freeze-
fracture, scanning electron
microscope, and thin-section
investigation of membrane structure.
The Journal of cell biology 1978, 76
(1), 158-74.
11

12. Highly-Stereotyped
Biophysically-driven Processes
Engulfment
Envelopment
Endocytosis
Exocytosis
Macropinocytosis
Vesiculation
Podokinesis
Transcellular Diapedesis
Immune Cell Activation
Fusion
Adhesion
Nutritive Endocytosis
Autophagy
12

13. Free Energy of Engulfment
where PB is the phagocyte-bacterium interfacial tension
and BL the bacterium-liquid interfacial tension.
An empirical Equation of State was developed for determining
interfacial tensions.
used in conjunction with Young’s equation
to obtain the interfacial tension between liquid and solid by
measuring the contact angle and surface tension of the liquid.
Absolom, Darryl R, Measurement of surface properties of phagocytes, bacteria, and other particles. In Methods in
Enzymology, Giovanni Di Sabato, J. E., Ed. Academic Press: 1986; Vol. Volume 132, pp 16-95. 13

14. Contact Angle and Surface Tension Measurement
yields the Free Energy of Engulfment
14

15. Absolom, Darryl
R, Measurement of
surface properties of
phagocytes, bacteria, an
d other particles. In
Methods in
Enzymology, Giovanni
Di Sabato, J. E., Ed.
Academic Press: 1986;
Vol. Volume 132, pp 16-
95.
15

16. Interfacial Water Stress
We refer to water stress as a property
of interfacial water - interfacial
tension - which destabilizes
enzymes, protein structure, and cell
membranes
16

17. Intravital Microscopy
W T Coakley, et al. have detected wave
phenomena at the biointerfaces of RBCs,
platelets, and endothelial cells.
The glycocalyx layers surrounding our cell
membranes have been shown by intravital
microscopists to have properties similar to
the massive EZs discovered by Gerald
Pollack.
17

18. 18

19. Average number of waves per
wavy cell rim…
“…decreased when cell surface charge was
depleted, when polyvalent cations were in the
suspending phase, and when cationic drugs
were present, and increased in the presence of
anionic drugs.”
Gallez, D.; Coakley, W. T., Interfacial instability at cell
membranes. Progress in Biophysics and Molecular Biology
1986, 48 (3), 155-199.
19

20. Wave Phenomena, Energy and Water Stressors
• Wave phenomena have been detected at the biointerfaces
of RBCs, platelets, and endothelial cells
- Longer wavelengths in the membrane imply lower energy
- Lower energy implies energy-unloading of the membrane
- Higher surface tension implies intramembrane instability, longer
wavelengths, and lower energy in the membrane.
- Lower surface tension implies intramembrane stability, shorter
wavelengths, and greater energy in the membrane.
• Exogenous interfacial water "stressors" in the low
micromolar concentration range energy-unload our cell
membranes.
• Examples of exogenous interfacial water stressors:
- Polycationic surfactants (strong kosmotropic cations)
- Certain non-ionic surfactants (especially in the low pH range)
20

21. Wave Phenomena at Bio-interfaces
Biophysical Manifestations of Cellular Stress
• Quantum coherent bio-interfacial
water is resonating in-phase over
all timescales.
• The Wave Equation applies.
21

22. The Wave Equation
e = c x h/
where is wavelength, h is Planck's
constant, and c is the speed of
light, indicates that the longer the
wavelength, the lower the energy.
22

23. Hypothesis
 Endothelial Glycocalyx Layers (EGL)
described by intravital microscopists
represent Exclusion Zones (EZs) analogous
to those described by Gerald Pollack.
 Interfacial water found in membrane-
bound caveolae of lipid rafts provides a
quantum coherent ensemble of Coherence
Domains (CDs) analogous to those
described by Emilio Del Giudice.
23

24. Hypothesis
A modified dissipative version of the wave
equation applies to:
 wave phenomena in cell membranes
 waves in EZs
 waves in a quantum coherent ensemble of
CDs.
Waves in the RBC membrane are coherent
with waves in the EZ and CD around the RBC
membrane.
24

25. Quantum coherent Bio-interfacial Waves
Resonating in phase, even though the
time scales may be vastly different
between the membrane, EZ, and CD
waves.
25

26. An Important Role for Cholesterol Sulfate
Cholesterol Sulfate (Ch-S) reduces interfacial
instability at cell membranes by reducing Exogenous
Interfacial Water Stress (EIWS).
When the intramembrane wavelength is longer, the
intramembrane energy is lower, and the exogenous
interfacial water stressors are energy-unloading the
membrane, i.e. energy-unloading the exclusions zones
(EZs) and coherence domains (CDs) of our cell
membranes.
26

27. Cholesterol Sulfate (Ch-S) reduces
interfacial instability at cell
membranes by reducing Exogenous
Interfacial Water Stress (EIWS).
Hydrophobic core
Kosmotropic anion
27

28. 28

29. (a) Scanning electron micrograph of human erythrocytes in
hypotonic saline solution. X 10,000.
(b) Scanning electron micrograph of human erythrocytes in
hypotonic saline solution. X 20,000.
(c) Scanning electron micrograph of human erythrocytes in
hypotonic saline solution in presence of 10-5 M
cholesterol sulfate. X 10,000.
Bleau, G.; Lalumiure, G.; Chapdelaine, A.; Roberts, K., Red
cell surface structure. Stabilization by cholesterol sulfate as
evidenced by scanning electron microscopy. Biochimica et
biophysica acta 1975, 375 (2), 220-3. 29

30. 30

31. 31

32. 32

33. Brecher, G.; Bessis, M., Present status of spiculed red cells and their relationship to the discocyte-echinocyte transformation:
a critical review. Blood 1972, 40 (3), 333-44. 33

34. 34

35. 35

36. 36

37. SEM image of a red blood cell and a white blood cell stacked on top of the red blood cell.
Adapted from John F. Lesoine, “Electron Microscopy of Human Blood Cells”
http://www.optics.rochester.edu/workgroups/cml/opt307/spr06/john/lesoineTEMSEM.hm
37

38. An SEM image showing two different stages of a platelet becoming activated.
Adapted from John F. Lesoine, “Electron Microscopy of Human Blood Cells”
http://www.optics.rochester.edu/workgroups/cml/opt307/spr06/john/lesoineTEMSEM.htm
38

39. Adapted from John F. Lesoine, “Electron Microscopy of Human Blood Cells”
http://www.optics.rochester.edu/workgroups/cml/opt307/spr06/john/lesoineTEMSEM.htm 39

40. Some Clinically-important Observations
Predicted by the Jones-Ray Effect
 Molecular Mimicry of Cholesterol Sulfate
 Membrane stabilization by Cholesterol Sulfate of RBC
membranes subjected to hypotonic stress
 Effect of free fatty acids on Erythrocytes
- Erythrocytes protected against hypotonic hemolysis in low
concentration range, but opposite effect in high concentration
- Biphasic free fatty acid chain length dependence observed in human
erythrocytes.
 Sulfated neurosteroids are potent non-competitive
antagonists of GABAA receptors without a clear structure–
activity relationship.
 Zeta potential measurements of blood samples may provide a
surrogate marker for interfacial tensions
40

41. Summary and Takeaway Message
 The Jones-Ray Effect is not accidental nor is it just a curiosity.
 The in vivo concentration of sulfate in arterial blood occurs at a
thermodynamic minimum in both the surface enhancement and the zeta
potential enhancement.
 The biphasic shape of the Jones-Ray and Zeta potential curves has
important implications for the role of the biosulfates in modulating
interfacial tension, membrane potential, and zeta potential of our blood.
 As a surrogate marker of interfacial tension, the biphasic Jones-Ray Effect
provides a plausible explanation as to why hydrophobic anions potently and
uncompetitively antagonize receptor function in the absence of a
conventional binding site.
41

42. 42